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1
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Sturgill I, Raab J, Hoadley K. Expanded detection and impact of BAP1 alterations in cancer. NAR Cancer 2024; 6:zcae045. [PMID: 39554490 PMCID: PMC11567159 DOI: 10.1093/narcan/zcae045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/15/2024] [Accepted: 11/06/2024] [Indexed: 11/19/2024] Open
Abstract
Aberrant expression of the BAP1 (BRCA associated protein 1) tumor suppressor gene is a prominent risk factor for several tumor types and is important in tumor evolution and progression. Here we performed integrated multi-omics analyses using data from The Cancer Genome Atlas for 33 cancer types and over 10 000 individuals to identify alterations leading to BAP1 disruption. We combined existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers, increasing somatic variant detection by 41% from 182 to 257, including 11 indels ≥40 bp. The expanded detection of mutations highlights the power of new tools to uncover longer indels and impactful mutations. We developed an expression-based BAP1 activity score and identified a transcriptional profile associated with BAP1 disruption in cancer. BAP1 has been proposed to play a critical role in controlling tumor plasticity and normal cell fate. Leveraging human and mouse liver datasets, BAP1 loss in normal cells resulted in lower BAP1 activity scores and lower scores were associated with a less-differentiated phenotype in embryonic cells. Together, our expanded BAP1 mutant samples revealed a transcriptional signature in cancer cells, supporting BAP1's influences on cellular plasticity and cell identity maintenance.
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Affiliation(s)
- Ian R Sturgill
- Bioinformatics and Computational Biology Curriculum, Department of Genetics, University of North Carolina at Chapel Hill, 116 Manning Drive, Chapel Hill, NC 27599, USA
| | - Jesse R Raab
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 116 Manning Drive, Chapel Hill, NC 27599, USA
| | - Katherine A Hoadley
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 116 Manning Drive, Chapel Hill, NC 27599, USA
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2
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Hwang J, Lee HE, Han JS, Choi MH, Hong SH, Kim SW, Yang JH, Park U, Jung ES, Choi YJ. Sex-specific survival gene mutations are discovered as clinical predictors of clear cell renal cell carcinoma. Sci Rep 2024; 14:15800. [PMID: 38982123 PMCID: PMC11233666 DOI: 10.1038/s41598-024-66525-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/02/2024] [Indexed: 07/11/2024] Open
Abstract
Although sex differences have been reported in patients with clear cell renal cell carcinoma (ccRCC), biological sex has not received clinical attention and genetic differences between sexes are poorly understood. This study aims to identify sex-specific gene mutations and explore their clinical significance in ccRCC. We used data from The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma (TCGA-KIRC), The Renal Cell Cancer-European Union (RECA-EU) and Korean-KIRC. A total of 68 sex-related genes were selected from TCGA-KIRC through machine learning, and 23 sex-specific genes were identified through verification using the three databases. Survival differences according to sex were identified in nine genes (ACSS3, ALG13, ASXL3, BAP1, JADE3, KDM5C, KDM6A, NCOR1P1, and ZNF449). Female-specific survival differences were found in BAP1 in overall survival (OS) (TCGA-KIRC, p = 0.004; RECA-EU, p = 0.002; and Korean-KIRC, p = 0.003) and disease-free survival (DFS) (TCGA-KIRC, p = 0.001 and Korean-KIRC, p = 0.000004), and NCOR1P1 in DFS (TCGA-KIRC, p = 0.046 and RECA-EU, p = 0.00003). Male-specific survival differences were found in ASXL3 (OS, p = 0.017 in TCGA-KIRC; and OS, p = 0.005 in RECA-EU) and KDM5C (OS, p = 0.009 in RECA-EU; and DFS, p = 0.016 in Korean-KIRC). These results suggest that biological sex may be an important predictor and sex-specific tailored treatment may improve patient care in ccRCC.
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Affiliation(s)
- Jia Hwang
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 06591, Republic of Korea
| | - Hye Eun Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 06591, Republic of Korea
| | - Jin Seon Han
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 06591, Republic of Korea
| | - Moon Hyung Choi
- Department of Radiology, College of Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, 03312, Republic of Korea
| | - Sung Hoo Hong
- Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Sae Woong Kim
- Department of Urology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea
| | - Ji Hoon Yang
- Department of Computer Science and Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Unsang Park
- Department of Computer Science and Engineering, Sogang University, Seoul, 04107, Republic of Korea
| | - Eun Sun Jung
- Department of Hospital Pathology, College of Medicine, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, 03312, Republic of Korea
| | - Yeong Jin Choi
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 06591, Republic of Korea.
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3
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Dagogo-Jack I. Targeted Approaches to Treatment of Pleural Mesothelioma: A Review. JCO Precis Oncol 2023; 7:e2300344. [PMID: 37992257 PMCID: PMC10681489 DOI: 10.1200/po.23.00344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/16/2023] [Accepted: 09/11/2023] [Indexed: 11/24/2023] Open
Abstract
Pleural mesothelioma is an aggressive disease that is enriched for inactivating alterations in tumor suppressor genes. Systemic therapeutic strategies for pleural mesothelioma generally involve chemotherapies and immunotherapies that are chosen without consideration of the tumor's molecular profile. As this generalized approach to treatment rarely yields durable responses, alternative therapeutic regimens are urgently indicated. Preclinical studies have identified synthetic lethal protein and metabolic interactions, recurrently overexpressed proteins, and frequent pathway perturbations that may be therapeutically exploited in mesothelioma. This review discusses the mechanism of action of emerging investigational therapies and summarizes findings from phase I-II clinical trials exploring selective, biomarker-driven therapeutic strategies for mesothelioma, with a focus on five common targets. Finally, using lessons learned from these clinical trials, imperatives for successful implementation of targeted therapy in mesothelioma are discussed.
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Affiliation(s)
- Ibiayi Dagogo-Jack
- Department of Medicine, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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4
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Barnett SE, Kenyani J, Tripari M, Butt Z, Grosman R, Querques F, Shaw L, Silva LC, Goate Z, Marciniak SJ, Rassl DM, Jackson R, Lian LY, Szlosarek PW, Sacco JJ, Coulson JM. BAP1 Loss Is Associated with Higher ASS1 Expression in Epithelioid Mesothelioma: Implications for Therapeutic Stratification. Mol Cancer Res 2023; 21:411-427. [PMID: 36669126 PMCID: PMC10150242 DOI: 10.1158/1541-7786.mcr-22-0635] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 12/20/2022] [Accepted: 01/19/2023] [Indexed: 01/21/2023]
Abstract
The nuclear deubiquitylase BRCA1-associated protein 1 (BAP1) is frequently inactivated in malignant pleural mesothelioma (MPM) and germline BAP1 mutation predisposes to cancers including MPM. To explore the influence on cell physiology and drug sensitivity, we sequentially edited a predisposition mutation (w-) and a promoter trap (KO) into human mesothelial cells. BAP1w-/KO MeT5A cells express less BAP1 protein and phenocopy key aspects of BAP1 loss in MPM. Stable isotope labeling with amino acids in cell culture-mass spectrometry revealed evidence of metabolic adaptation, with concomitant alteration of cellular metabolites. In MeT5A, BAP1 deficiency reduces glycolytic enzyme levels but increases enzymes involved in the tricarboxylic acid cycle and anaplerotic pathways. Notably both argininosuccinate synthase 1 (ASS1), essential for cellular synthesis of arginine, and its substrate aspartate, are elevated in BAP1w-/KO MeT5A cells. Likewise, ASS1 expression is higher in BAP1-altered MPM cell lines, and inversely correlates with BAP1 in The Cancer Genome Atlas MESO dataset. Elevated ASS1 is also evident by IHC staining in epithelioid MPM lacking nuclear BAP1 expression, with improved survival among patients with BAP1-negative/ASS1-expressing tumors. Alterations in arginine metabolism may sensitize cells to metabolic drugs and we find that BAP1-negative/ASS1-expressing MPM cell lines are more sensitive to ASS1 inhibition, although not to inhibition of purine synthesis by mizoribine. Importantly, BAP1w-/KO MeT5A become desensitized to arginine deprivation by pegylated arginine deiminase (ADI-PEG20), phenocopying BAP1-negative/ASS1-expressing MPM cell lines. IMPLICATIONS Our data reveal an interrelationship between BAP1 and arginine metabolism, providing a potential means of identifying patients with epithelioid MPM likely to benefit from ADI-PEG20.
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Affiliation(s)
- Sarah E. Barnett
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Jenna Kenyani
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Martina Tripari
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Zohra Butt
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Rudi Grosman
- Biochemistry and Systems Biology, University of Liverpool, Liverpool, United Kingdom
| | - Francesca Querques
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Liam Shaw
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Luisa C. Silva
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Zoe Goate
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
| | - Stefan J. Marciniak
- Cambridge Institute for Medical Research, Cambridge, United Kingdom
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Doris M. Rassl
- Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Richard Jackson
- Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Liverpool Clinical Trials Centre, University of Liverpool, Liverpool, United Kingdom
| | - Lu-Yun Lian
- Biochemistry and Systems Biology, University of Liverpool, Liverpool, United Kingdom
| | - Peter W. Szlosarek
- Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Joseph J. Sacco
- Molecular and Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, United Kingdom
- Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom
| | - Judy M. Coulson
- Molecular Physiology and Cell Signalling, University of Liverpool, Liverpool, United Kingdom
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5
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Carapeto F, Bozorgui B, Shroff RT, Chagani S, Soto LS, Foo WC, Wistuba I, Meric-Bernstam F, Shalaby A, Javle M, Korkut A, Kwong LN. The immunogenomic landscape of resected intrahepatic cholangiocarcinoma. Hepatology 2022; 75:297-308. [PMID: 34510503 PMCID: PMC8766948 DOI: 10.1002/hep.32150] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 07/31/2021] [Accepted: 08/16/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Cholangiocarcinoma (CCA) is a deadly and highly therapy-refractory cancer of the bile ducts, with early results from immune checkpoint blockade trials showing limited responses. Whereas recent molecular assessments have made bulk characterizations of immune profiles and their genomic correlates, spatial assessments may reveal actionable insights. APPROACH AND RESULTS Here, we have integrated immune checkpoint-directed immunohistochemistry with next-generation sequencing of resected intrahepatic CCA samples from 96 patients. We found that both T-cell and immune checkpoint markers are enriched at the tumor margins compared to the tumor center. Using two approaches, we identify high programmed cell death protein 1 or lymphocyte-activation gene 3 and low CD3/CD4/inducible T-cell costimulator specifically in the tumor center as associated with poor survival. Moreover, loss-of-function BRCA1-associated protein-1 mutations are associated with and cause elevated expression of the immunosuppressive checkpoint marker, B7 homolog 4. CONCLUSIONS This study provides a foundation on which to rationally improve and tailor immunotherapy approaches for this difficult-to-treat disease.
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Affiliation(s)
- Fernando Carapeto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Behnaz Bozorgui
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Rachna T Shroff
- Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724, USA
| | - Sharmeen Chagani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Luisa Solis Soto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wai Chin Foo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ignacio Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ahmed Shalaby
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Milind Javle
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anil Korkut
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Lawrence N Kwong
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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6
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Yan YC, Meng GX, Ding ZN, Liu YF, Chen ZQ, Yan LJ, Yang YF, Liu H, Yang CC, Dong ZR, Hong JG, Li T. Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies. J Cancer 2022; 13:88-101. [PMID: 34976173 PMCID: PMC8692694 DOI: 10.7150/jca.65574] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 11/10/2021] [Indexed: 12/16/2022] Open
Abstract
BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.
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Affiliation(s)
- Yu-Chuan Yan
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Guang-Xiao Meng
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Zi-Niu Ding
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Yan-Feng Liu
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Zhi-Qiang Chen
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Lun-Jie Yan
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Ya-Fei Yang
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Hui Liu
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Chun-Cheng Yang
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Zhao-Ru Dong
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Jian-Guo Hong
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China
| | - Tao Li
- Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R. China.,Department of hepatobiliary surgery, The second Hospital of Shandong University, Jinan 250012, P.R. China
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7
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Hajj GNM, Cavarson CH, Pinto CAL, Venturi G, Navarro JR, Lima VCCD. Malignant pleural mesothelioma: an update. J Bras Pneumol 2021; 47:e20210129. [PMID: 34909922 PMCID: PMC8836658 DOI: 10.36416/1806-3756/e20210129] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 09/11/2021] [Indexed: 12/14/2022] Open
Abstract
Malignant mesotheliomas are rare types of cancers that affect the mesothelial surfaces, usually the pleura and peritoneum. They are associated with asbestos exposure, but due to a latency period of more than 30 years and difficult diagnosis, most cases are not detected until they reach advanced stages. Treatment options for this tumor type are very limited and survival ranges from 12 to 36 months. This review discusses the molecular physiopathology, current diagnosis, and latest therapeutic options for this disease.
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Affiliation(s)
- Glaucia N M Hajj
- Instituto International de Pesquisa, A.C. Camargo Cancer Center, São Paulo (SP), Brasil.,Instituto Nacional de Oncogenômica e Inovação Terapêutica, São Paulo (SP), Brasil
| | - Carolina H Cavarson
- Instituto International de Pesquisa, A.C. Camargo Cancer Center, São Paulo (SP), Brasil.,Instituto Nacional de Oncogenômica e Inovação Terapêutica, São Paulo (SP), Brasil
| | | | - Gabriela Venturi
- Instituto International de Pesquisa, A.C. Camargo Cancer Center, São Paulo (SP), Brasil.,BP Mirante, São Paulo (SP), Brasil
| | | | - Vladmir C Cordeiro de Lima
- Instituto Nacional de Oncogenômica e Inovação Terapêutica, São Paulo (SP), Brasil.,Rede D'Or, São Paulo (SP), Brasil
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8
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A Critical Assessment of Current Grading Schemes for Diffuse Pleural Mesothelioma With a Proposal for a Novel Mesothelioma Weighted Grading Scheme (MWGS). Am J Surg Pathol 2021; 46:774-785. [PMID: 34907994 DOI: 10.1097/pas.0000000000001854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Although there is early support for schemes based on nuclear grade, necrosis and mitotic rate, there is currently no widely implemented grading system for diffuse pleural mesothelioma (DPM). We investigated current systems and propose a novel Mesothelioma Weighted Grading Scheme (MWGS). The MWGS assigns weighted scores from 0 to 10 based on age (≤74, >74 yrs: 0,1); histologic type (epithelioid, biphasic, sarcomatoid: 0,1,2); necrosis (absent, present: 0,2); mitotic count per 2 mm2 (≤1, 2 to 4, ≥5: 0,1,2); nuclear atypia (mild, moderate, severe: 0,1,2); and BRCA1-associated protein 1 (BAP1) expression (lost, retained: 0,1). A score of 0 to 3 is low grade, 4 to 6 intermediate grade, and 7 to 10 high grade. In 369 consecutive DPMs, median survival was 17.1, 10.1, and 4.1 months for low, intermediate, and high grades (P<0.0001). A progressive increase in score correlated with worsening overall survival (P<0.0001). Interobserver concordance was substantial (κ=0.588), with assessment of nuclear grade being the most subjective parameter (κ=0.195). We compared the MWGS to the 2-tiered system discussed in the World Health Organization (WHO) fifth edition. The WHO system predicted median survival in epithelioid (median 18.0 vs. 11.3 mo, P=0.003) and biphasic (16.2 vs. 4.2 mo, P=0.002), but not sarcomatoid DPM (5.4 vs. 4.7 mo, P=0.407). Interestingly, the WHO grading system was prognostic in cases with BAP1 loss (median survival 18.7 vs. 10.4 mo, P<0.0001), but not retained BAP1 expression (8.9 vs. 6.2 mo, P=0.061). In conclusion, the WHO scheme has merit in epithelioid/biphasic and BAP1-deficient DPM, however, the MWGS can be used for risk stratification of all DPMs, regardless of histologic subtype and BAP1 status.
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9
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Marcus R, Ferri-Borgogno S, Hosein A, Foo WC, Ghosh B, Zhao J, Rajapakshe K, Brugarolas J, Maitra A, Gupta S. Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2021; 13:cancers13225709. [PMID: 34830866 PMCID: PMC8616431 DOI: 10.3390/cancers13225709] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/12/2021] [Accepted: 11/12/2021] [Indexed: 12/21/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p < 0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
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Affiliation(s)
- Rebecca Marcus
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Department of Surgical Oncology, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
- Correspondence:
| | - Sammy Ferri-Borgogno
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Abdel Hosein
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Advocate Aurora Health, Vince Lombardi Cancer Clinic, Sheboygan, WI 53081, USA
| | - Wai Chin Foo
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Bidyut Ghosh
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - Jun Zhao
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - Kimal Rajapakshe
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Anirban Maitra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sonal Gupta
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; (S.F.-B.); (A.H.); (B.G.); (J.Z.); (K.R.); (A.M.); (S.G.)
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10
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Diori Karidio I, Sanlier SH. Reviewing cancer's biology: an eclectic approach. J Egypt Natl Canc Inst 2021; 33:32. [PMID: 34719756 DOI: 10.1186/s43046-021-00088-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 09/11/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cancer refers to a group of some of the worldwide most diagnosed and deadliest pathophysiological conditions that conquered researchers' attention for decades and yet begs for more questions for a full comprehension of its complex cellular and molecular pathology. MAIN BODY The disease conditions are commonly characterized by unrestricted cell proliferation and dysfunctional replicative senescence pathways. In fact, the cell cycle operates under the rigorous control of complex signaling pathways involving cyclins and cyclin-dependent kinases assumed to be specific to each phase of the cycle. At each of these checkpoints, the cell is checked essentially for its DNA integrity. Genetic defects observed in these molecules (i.e., cyclins, cyclin-dependent kinases) are common features of cancer cells. Nevertheless, each cancer is different concerning its molecular and cellular etiology. These could range from the genetic defects mechanisms and/or the environmental conditions favoring epigenetically harbored homeostasis driving tumorigenesis alongside with the intratumoral heterogeneity with respect to the model that the tumor follows. CONCLUSIONS This review is not meant to be an exhaustive interpretation of carcinogenesis but to summarize some basic features of the molecular etiology of cancer and the intratumoral heterogeneity models that eventually bolster anticancer drug resistance for a more efficient design of drug targeting the pitfalls of the models.
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Affiliation(s)
- Ibrahim Diori Karidio
- Department of Biochemistry, Faculty of Science, E Block, Ege University, Erzene Mahallesi, Bornova, 35040, Izmir, Turkey.
| | - Senay Hamarat Sanlier
- Department of Biochemistry, Faculty of Science, E Block, Ege University, Erzene Mahallesi, Bornova, 35040, Izmir, Turkey.,ARGEFAR, Faculty of Medicine, Ege University, Bornova, 35040, Izmir, Turkey
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11
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Bai J, Chen Z, Chen C, Zhang M, Zhang Y, Song J, Yuan J, Jiang X, Xing W, Yang J, Bai J, Zhou Y. Reducing hyperactivated BAP1 attenuates mutant ASXL1-driven myeloid malignancies in human haematopoietic cells. Cancer Lett 2021; 519:78-90. [PMID: 34186160 DOI: 10.1016/j.canlet.2021.06.019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 11/16/2022]
Abstract
Additional sex combs-like 1 (ASXL1) is frequently mutated in a variety of myeloid malignancies, resulting in expression of a C-terminal-truncated ASXL1 protein that confers gain of function on the ASXL1-BAP1 deubiquitinase (DUB) complex. Several studies have reported that hyperactivity of BRCA-1-associated protein 1 (BAP1) in deubiquitinating mono-ubiquitinated histone H2AK119 is one of the critical molecular mechanisms in ASXL1 mutation-driven myeloid malignancies in mice. In this study, we found that human haematopoietic stem and progenitor cells (HSPCs) overexpressing truncated ASXL1 (ASXL1Y591X) developed an MDS-like phenotype similar to that induced by overexpression of BAP1. We then used shRNAs targeting BAP1 in ASXL1Y591X-overexpressing HSPCs and primary leukaemia cells with ASXL1 mutation, demonstrating that reduced BAP1 expression can partially rescue the pathological consequences. RNA sequencing and chromatin immunoprecipitation coupled with quantitative PCR analyses revealed that reduced BAP1 expression suppressed upregulation of the transcription factors AP-1 and EGR1/2, as well as myeloid dysplasia-associated genes, by retarding H2AK119Ub removal caused by ASXL1 mutation. This study indicates that targeting the hyperactive ASXL1-BAP1 DUB complex can attenuate mutant ASXL1-driven myeloid malignancies in human.
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Affiliation(s)
- Jiaojiao Bai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Zizhen Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Chao Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Mingying Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yuhui Zhang
- Department of Hematology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Junzhe Song
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jiajia Yuan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiao Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Wen Xing
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jing Yang
- International Cooperation Laboratory of Stem Cell Research, Hebei Medical University, Shijiazhuang, 050017, China
| | - Jie Bai
- Department of Hematology, The Second Affiliated Hospital of Tianjin Medical University, Tianjin, 300211, China.
| | - Yuan Zhou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
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12
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Zaayman M, Nguyen P, Silfvast-Kaiser A, Frieder J, West C, Tumminello K, Paek SY. BAPoma presenting as an incidental scalp papule: case report, literature review, and screening recommendations for BAP1 tumor predisposition syndrome. J DERMATOL TREAT 2021; 33:1855-1860. [PMID: 34106034 DOI: 10.1080/09546634.2021.1939847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVE BRCA1-associated protein 1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is associated with an increased risk for aggressive cancers. BAP1-inactivated melanocytic tumors (BIMTs) are observed in 75% of BAP1-TPDS, often presenting as early as the second decade of life. These lesions may serve as a predictive marker to identify patients who carry germline BAP1 mutations and thus are at higher risk of developing associated cancers. Early diagnosis for these malignancies is crucial for curative treatment. METHODS We report a patient who presented with an incidental scalp papule for which biopsy was consistent with a BIMT. A review of literature was conducted by accessing the PubMed database to delineate present knowledge of BIMTs, assess recommendations for screening of germline BAP1 mutations, and evaluate cancer surveillance strategies for BAP1-TPDS associated cancers. RESULTS Consensus in literature indicates that genetic evaluation should be encouraged in patients presenting with multiple BIMTs or a new BIMT with significant family history of BAP1-TPDS related cancers. If positive for a germline BAP1 mutation, cancer surveillance should be recommended for early diagnosis and timely intervention. CONCLUSIONS Further workup should be encouraged in patients who meet the proposed screening criteria for germline BAP1 mutations. Patients could benefit from cancer surveillance for earlier diagnosis, management, and improved outcomes.
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Affiliation(s)
- Marcus Zaayman
- Division of Dermatology, Baylor Scott & White, Dallas, TX, USA
| | - Peter Nguyen
- College of Medicine, Texas A&M University, Dallas, TX, USA
| | | | - Jillian Frieder
- Division of Dermatology, Baylor Scott & White, Dallas, TX, USA
| | | | | | - So Yeon Paek
- Division of Dermatology, Baylor Scott & White, Dallas, TX, USA.,College of Medicine, Texas A&M University, Dallas, TX, USA
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13
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Wang F, Luo M, Qu H, Cheng Y. BAP1 promotes viability and migration of ECA109 cells through KLF5/CyclinD1/FGF-BP1. FEBS Open Bio 2021; 11:1497-1503. [PMID: 33529461 PMCID: PMC8091813 DOI: 10.1002/2211-5463.13105] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/28/2020] [Accepted: 01/29/2021] [Indexed: 11/11/2022] Open
Abstract
More than 40 000 patients worldwide die from esophageal cancer annually. The 5-year survival rate of patients is only ~ 15-20%, and thus, there is an ongoing need to improve diagnosis and treatment of esophageal cancer. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is a marker of poor prognosis in several cancers, including uveal melanoma, renal cell carcinoma, cholangiocarcinoma, non-small cell lung cancer, and colorectal cancer. BAP1 mutations are early and rare events in esophageal carcinoma, but the involvement of BAP1 in progression of esophageal carcinoma is unclear. Here, we report that cell proliferation and migration were significantly enhanced in esophageal carcinoma ECA109 cells overexpressing BAP1, while they were diminished upon BAP1 knockdown. In addition, the expression of Krüppel-like factor 5 (KLF5), CyclinD1, and FGF-BP1 was increased by BAP1 overexpression and decreased by BAP1 knockdown. Our data suggest that BAP1 promotes cell proliferation and migration, and enhances the expression of KLF5 and its downstream genes, including CyclinD1 and FGF-BP1, in the esophageal carcinoma cell line ECA109.
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Affiliation(s)
- Fengyun Wang
- Cheeloo College of Medicine, Qilu Hospital, ShanDong University, China
| | - Ming Luo
- The Third Affiliated Hospital of BaoTou Medical College, Mongolia, China
| | - Honglan Qu
- Inner Mongolia Agricultural Hospital, YaKeShi, China
| | - Yufeng Cheng
- Cheeloo College of Medicine, Qilu Hospital, ShanDong University, China
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14
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Hu XM, Li ZX, Lin RH, Shan JQ, Yu QW, Wang RX, Liao LS, Yan WT, Wang Z, Shang L, Huang Y, Zhang Q, Xiong K. Guidelines for Regulated Cell Death Assays: A Systematic Summary, A Categorical Comparison, A Prospective. Front Cell Dev Biol 2021; 9:634690. [PMID: 33748119 PMCID: PMC7970050 DOI: 10.3389/fcell.2021.634690] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Over the past few years, the field of regulated cell death continues to expand and novel mechanisms that orchestrate multiple regulated cell death pathways are being unveiled. Meanwhile, researchers are focused on targeting these regulated pathways which are closely associated with various diseases for diagnosis, treatment, and prognosis. However, the complexity of the mechanisms and the difficulties of distinguishing among various regulated types of cell death make it harder to carry out the work and delay its progression. Here, we provide a systematic guideline for the fundamental detection and distinction of the major regulated cell death pathways following morphological, biochemical, and functional perspectives. Moreover, a comprehensive evaluation of different assay methods is critically reviewed, helping researchers to make a reliable selection from among the cell death assays. Also, we highlight the recent events that have demonstrated some novel regulated cell death processes, including newly reported biomarkers (e.g., non-coding RNA, exosomes, and proteins) and detection techniques.
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Affiliation(s)
- Xi-min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Zhi-xin Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Rui-han Lin
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Jia-qi Shan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Qing-wei Yu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Rui-xuan Wang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Lv-shuang Liao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wei-tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Zhen Wang
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Lei Shang
- Jiangxi Research Institute of Ophthalmology and Visual Sciences, Affiliated Eye Hospital of Nanchang University, Nanchang, China
| | - Yanxia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
- Hunan Key Laboratory of Ophthalmology, Changsha, China
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15
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Bazzichetto C, Luchini C, Conciatori F, Vaccaro V, Di Cello I, Mattiolo P, Falcone I, Ferretti G, Scarpa A, Cognetti F, Milella M. Morphologic and Molecular Landscape of Pancreatic Cancer Variants as the Basis of New Therapeutic Strategies for Precision Oncology. Int J Mol Sci 2020; 21:8841. [PMID: 33266496 PMCID: PMC7700259 DOI: 10.3390/ijms21228841] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023] Open
Abstract
To date, pancreatic cancer is still one of the most lethal cancers in the world, mainly due to the lack of early diagnosis and personalized treatment strategies. In this context, the possibility and the opportunity of identifying genetic and molecular biomarkers are crucial to improve the feasibility of precision medicine. In 2019, the World Health Organization classified pancreatic ductal adenocarcinoma cancer (the most common pancreatic tumor type) into eight variants, according to specific histomorphological features. They are: colloid carcinoma, medullary carcinoma, adenosquamous carcinoma, undifferentiated carcinoma, including also rhabdoid carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, hepatoid carcinoma, and signet-ring/poorly cohesive cells carcinoma. Interestingly, despite the very low incidence of these variants, innovative high throughput genomic/transcriptomic techniques allowed the investigation of both somatic and germline mutations in each specific variant, paving the way for their possible classification according also to specific alterations, along with the canonical mutations of pancreatic cancer (KRAS, TP53, CDKN2A, SMAD4). In this review, we aim to report the current evidence about genetic/molecular profiles of pancreatic cancer variants, highlighting their role in therapeutic and clinical impact.
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Affiliation(s)
- Chiara Bazzichetto
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (C.L.); (I.D.C.); (P.M.)
| | - Fabiana Conciatori
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Vanja Vaccaro
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Ilaria Di Cello
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (C.L.); (I.D.C.); (P.M.)
| | - Paola Mattiolo
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy; (C.L.); (I.D.C.); (P.M.)
| | - Italia Falcone
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Gianluigi Ferretti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Aldo Scarpa
- Department ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy;
| | - Francesco Cognetti
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; (C.B.); (V.V.); (I.F.); (G.F.); (F.C.)
| | - Michele Milella
- Division of Oncology, University of Verona, 37126 Verona, Italy;
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16
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Reddington CJ, Fellner M, Burgess AE, Mace PD. Molecular Regulation of the Polycomb Repressive-Deubiquitinase. Int J Mol Sci 2020; 21:ijms21217837. [PMID: 33105797 PMCID: PMC7660087 DOI: 10.3390/ijms21217837] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/20/2020] [Accepted: 10/20/2020] [Indexed: 12/16/2022] Open
Abstract
Post-translational modification of histone proteins plays a major role in histone–DNA packaging and ultimately gene expression. Attachment of ubiquitin to the C-terminal tail of histone H2A (H2AK119Ub in mammals) is particularly relevant to the repression of gene transcription, and is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here, we outline recent advances in the understanding of PR-DUB regulation, which have come through structural studies of the Drosophila melanogaster PR-DUB, biochemical investigation of the human PR-DUB, and functional studies of proteins that associate with the PR-DUB. In humans, mutations in components of the PR-DUB frequently give rise to malignant mesothelioma, melanomas, and renal cell carcinoma, and increase disease risk from carcinogens. Diverse mechanisms may underlie disruption of the PR-DUB across this spectrum of disease. Comparing and contrasting the PR-DUB in mammals and Drosophila reiterates the importance of H2AK119Ub through evolution, provides clues as to how the PR-DUB is dysregulated in disease, and may enable new treatment approaches in cancers where the PR-DUB is disrupted.
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17
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Santana LADM, Santana EMR, Albuquerque-Júnior RLCD, Takeshita WM, Braga Pereira N, Gomez RS, Gomes CC, de Sousa SF. Ameloblastoma shows nuclear BAP1 immunoexpression, independently of the BRAF V600E status. Oral Dis 2020; 27:1238-1242. [PMID: 32945606 DOI: 10.1111/odi.13644] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/21/2020] [Accepted: 09/07/2020] [Indexed: 12/13/2022]
Affiliation(s)
| | | | | | | | - Núbia Braga Pereira
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ricardo Santiago Gomez
- Oral Surgery and Pathology Department, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Carolina Cavaliéri Gomes
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Sílvia Ferreira de Sousa
- Oral Surgery and Pathology Department, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
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Abstract
Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy of the pleural lining associated with asbestos exposure in greater than 80% of cases. It is characterized by molecular heterogeneity both between patients and within individual tumors. Next-generation sequencing technology and novel computational techniques have resulted in a greater understanding of the epigenetic, genetic, and transcriptomic hallmarks of MPM. This article reviews these features and discusses the implications of advances in MPM molecular biology in clinical practice.
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Prabhakaran S, Hocking A, Kim C, Hussey M, Klebe S. The potential utility of GATA binding protein 3 for diagnosis of malignant pleural mesotheliomas. Hum Pathol 2020; 105:1-8. [PMID: 32888937 DOI: 10.1016/j.humpath.2020.08.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 08/24/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022]
Abstract
Malignant pleural mesothelioma is associated with asbestos exposure and poor outcomes. The usefulness of immunohistochemistry for diagnosis of sarcomatoid mesothelioma, especially the desmoplastic type, is limited, and more effective markers are required. GATA binding protein 3 (GATA3) has been suggested as a diagnostic marker for sarcomatoid mesothelioma. The potential usefulness of GATA3 for prognostication and its clinical and pathological correlations in different subtypes of mesothelioma have not been evaluated. We investigated the immunohistochemical labeling and associations for GATA3, BRCA1-associated protein 1 (BAP1), and Ki67 labeling in three major histological types of pleural malignant mesotheliomas. We examined 149 clinically annotated malignant mesotheliomas and assessed associations of GATA3 expression with clinical variables and prognosis. In addition, we labeled 10 cases of fibrous pleuritis with GATA3, all of which were negative. GATA3 was positive in 75 of 149 (50%) mesotheliomas, with the highest incidence of labeling seen in the sarcomatoid subtype (73%), compared with the biphasic (50%) and epithelioid (40%), mesotheliomas. A total of eight desmoplastic mesotheliomas showed labeling with GATA3. Patients whose tumors had sarcomatoid histology showed poorer survival than those with the other subtypes (p < 0.001), but overall GATA3 labeling did not have a statistically significant association with survival (p = 0.602). There was no association of GATA3 labeling and BAP1 status or Ki67 index. Our study includes the largest cohort of mesotheliomas that has been labeled for GATA3 to date. GATA3 is a useful marker for sarcomatoid mesothelioma, including the desmoplastic subtype. Discordance in GATA3 and BAP1 labeling of epithelioid and sarcomatoid components in the biphasic subtype is not uncommon.
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Affiliation(s)
- Sarita Prabhakaran
- Department of Anatomical Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, SA 5042, Australia.
| | - Ashleigh Hocking
- Department of Anatomical Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, SA 5042, Australia.
| | - Chankyung Kim
- Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, South Australia, SA 5042, Australia.
| | - Matthew Hussey
- Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, South Australia, SA 5042, Australia.
| | - Sonja Klebe
- Department of Surgical Pathology, SA Pathology at Flinders Medical Centre, Adelaide, South Australia, SA 5042, Australia; Department of Anatomical Pathology, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, SA 5042, Australia.
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20
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Cantini L, Pecci F, Murrone A, Tomasetti M, Copparoni C, Fiordoliva I, Morgese F, Rinaldi S, Mazzanti P, Rubini C, Cimadamore A, Barbisan F, Giampieri R, Scarpelli M, Santarelli L, Berardi R. Questioning the prognostic role of BAP-1 immunohistochemistry in malignant pleural mesothelioma: A single center experience with systematic review and meta-analysis. Lung Cancer 2020; 146:318-326. [PMID: 32622302 DOI: 10.1016/j.lungcan.2020.06.024] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The prognostic role of BRCA1 associated protein-1 (BAP1) expression in malignant pleural mesothelioma (MPM) is a matter of debate. We aimed to clarify whether MPM patients with loss of BAP1 expression have better overall survival (OS) compared to BAP1 positive patients. METHODS BAP1 immunohistochemical staining of tumor samples from 60 MPM patients treated at our institution with first-line chemotherapy was evaluated. A systematic literature search was also performed. Only cohort studies that investigated BAP1 by immunohistochemistry (IHC) and reported hazard ratio (HR) values for OS obtained through multivariate analysis (or adjusted for histotype) were considered. A dataset comprising 638 MPM patients was added to our cohort and included in the meta-analysis. RESULTS In our cohort, 23 samples (38 %) were BAP1 positive/retained (≥1 %) and 37 samples (62 %) were BAP1 negative/loss. BAP1 loss was associated with epithelioid histotype (p 0.01). Median OS times were 14.8 months (95 % CI: 10.7-29.3) and 18.1 months (95 % CI: 11.2-25.8) for negative and positive BAP1 expression, respectively (p 0.2). At multivariate analysis, again no differences were observed among the two groups (p 0.81). Similarly, the meta-analysis consisting of 698 patients showed no difference in terms of OS according to BAP1 status (HR 1.11; 95 % CI, 0·76-1·61; p 0.60). CONCLUSIONS BAP1 expression is not an independent prognostic factor for MPM patients and it should not be considered without taking into account tumor histotype. Future studies should investigate its predictive role in patients treated with new emerging therapies such as immunotherapy.
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Affiliation(s)
- Luca Cantini
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Federica Pecci
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Alberto Murrone
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Marco Tomasetti
- Department of Clinical and Molecular Sciences, Section of Experimental and Occupational Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60020, Ancona, Italy
| | - Cecilia Copparoni
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Ilaria Fiordoliva
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Francesca Morgese
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Silvia Rinaldi
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Paola Mazzanti
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Corrado Rubini
- Section of Pathological Anatomy, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Alessia Cimadamore
- Section of Pathological Anatomy, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Francesca Barbisan
- Section of Pathological Anatomy, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Riccardo Giampieri
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Marina Scarpelli
- Section of Pathological Anatomy, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy
| | - Lory Santarelli
- Department of Clinical and Molecular Sciences, Section of Experimental and Occupational Medicine, Università Politecnica delle Marche, Via Tronto 10/A, 60020, Ancona, Italy
| | - Rossana Berardi
- Clinical Oncology, Università Politecnica delle Marche, AOU Ospedali Riuniti, Via Conca 71, 60126, Ancona, Italy.
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Carbone M, Harbour JW, Brugarolas J, Bononi A, Pagano I, Dey A, Krausz T, Pass HI, Yang H, Gaudino G. Biological Mechanisms and Clinical Significance of BAP1 Mutations in Human Cancer. Cancer Discov 2020; 10:1103-1120. [PMID: 32690542 DOI: 10.1158/2159-8290.cd-19-1220] [Citation(s) in RCA: 180] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 02/03/2020] [Accepted: 05/07/2020] [Indexed: 11/16/2022]
Abstract
Among more than 200 BAP1-mutant families affected by the "BAP1 cancer syndrome," nearly all individuals inheriting a BAP1 mutant allele developed one or more malignancies during their lifetime, mostly uveal and cutaneous melanoma, mesothelioma, and clear-cell renal cell carcinoma. These cancer types are also those that, when they occur sporadically, are more likely to carry somatic biallelic BAP1 mutations. Mechanistic studies revealed that the tumor suppressor function of BAP1 is linked to its dual activity in the nucleus, where it is implicated in a variety of processes including DNA repair and transcription, and in the cytoplasm, where it regulates cell death and mitochondrial metabolism. BAP1 activity in tumor suppression is cell type- and context-dependent. BAP1 has emerged as a critical tumor suppressor across multiple cancer types, predisposing to tumor development when mutated in the germline as well as somatically. Moreover, BAP1 has emerged as a key regulator of gene-environment interaction.This article is highlighted in the In This Issue feature, p. 1079.
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Affiliation(s)
| | - J William Harbour
- Bascom Palmer Eye Institute, Sylvester Comprehensive Cancer Center, and Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida
| | - James Brugarolas
- Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Angela Bononi
- University of Hawai'i Cancer Center, Honolulu, Hawai'i
| | - Ian Pagano
- University of Hawai'i Cancer Center, Honolulu, Hawai'i
| | - Anwesha Dey
- Department of Discovery Oncology, Genentech, South San Francisco, California
| | - Thomas Krausz
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Harvey I Pass
- Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York
| | - Haining Yang
- University of Hawai'i Cancer Center, Honolulu, Hawai'i
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Oh H, Lee YJ, Kang SG, Ahn B, Kim E, Chae YS, Lee Y, Lee JH, Kim CH. BRCA1-associated protein 1 expression and prognostic role in prostate adenocarcinoma. Investig Clin Urol 2020; 61:166-172. [PMID: 32158967 PMCID: PMC7052417 DOI: 10.4111/icu.2020.61.2.166] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 11/02/2019] [Indexed: 12/24/2022] Open
Abstract
Purpose As prostate cancer (PCa) is the second most commonly diagnosed cancer worldwide, finding novel markers for prognosis is crucial. BRCA1-associated protein 1 (BAP-1), a nuclear-localized deubiquitinating enzyme, has been reported in several human cancers. However, its prognostic role in PCa remains unknown. Herein, we assessed the prognostic and clinicopathologic significance of BAP-1 in PCa. Materials and Methods Seventy surgical specimens from radical prostatectomy cases were examined. Two cores per case were selected for construction of tissue microarrays (TMAs). After the exclusion of two cases because of tissue sparsity, BAP-1 immunohistochemical expression was evaluated in 68 cases of formalin-fixed, paraffin-embedded TMA tissue blocks. The immunohistochemical stain was scored according to proportion of nuclear staining: negative (<10% of tumor cells) or positive (≥10% of tumor cells). Results BAP-1 expression was negative in 30 cases (44.1%) and positive in 38 cases (55.9%). Positive BAP-1 expression was more common in pT3b disease than in pT2 (p=0.038). A high preoperative prostate-specific antigen level was correlated with BAP-1 expression (p=0.014). Age, lymphovascular invasion, perineural invasion, and grade group were not significantly correlated with BAP-1 expression. Patients with positive BAP-1 expression showed significantly shorter disease-free survival (p=0.013). Additionally, BAP-1 was an independent prognostic factor of PCa (p=0.035; hazard ratio, 9.277; 95% confidence interval, 1.165–73.892). Conclusions Our study findings showed an association of BAP-1 expression with poor PCa prognosis and suggest a potential role for BAP-1 as a prognostic biomarker for PCa.
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Affiliation(s)
- Harim Oh
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Yoo Jin Lee
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sung Gu Kang
- Department of Urology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Bokyung Ahn
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Eojin Kim
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Yang-Seok Chae
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Youngseok Lee
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jeong Hyeon Lee
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chul Hwan Kim
- Department of Pathology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
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Maffeis V, Cappellesso R, Nicolè L, Guzzardo V, Menin C, Elefanti L, Schiavi F, Guido M, Fassina A. Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations. Endocr Pathol 2019; 30:276-284. [PMID: 31734934 DOI: 10.1007/s12022-019-09595-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Breast cancer-associated protein 1 (BAP1) gene is a broad-spectrum tumor suppressor. Indeed, its loss of expression, due to biallelic inactivating mutations or deletions, has been described in several types of tumors including melanoma, malignant mesothelioma, renal cell carcinoma, and others. There are so far only two reports of BAP1-mutated paraganglioma, suggesting the possible involvement of this gene in paraganglioma (PGL) and pheochromocytoma (PCC) pathogenesis. We assessed BAP1 expression by immunohistochemistry (IHC) in a cohort of 56 PCC/PGL patients (and corresponding metastases, when available). Confirmatory Sanger sequencing (exons 1-17) of BAP1 has been performed in those samples which resulted negative by IHC. BAP1 nuclear expression was lost in 2/22 (9.1%) PGLs and in 12/34 (35.3%) PCCs, five of which harboring a germline mutation predisposing the development of such tumors (MENIN, MAX, SDHB, SDHD, and RET gene). Confirmatory Sanger sequencing revealed the wild-type BAP1 status of all the analyzed samples. No heterogeneity between primary and metastatic tissue was observed. This study documents that the loss of BAP1 nuclear expression is quite a frequent finding in PCC/PGL, suggesting a possible role of BAP1 in the pathogenesis of these tumors. Gene mutations do not seem to be involved in this loss of expression, at least in most cases. Other genetic and epigenetic mechanisms need to be further investigated.
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Affiliation(s)
- Valeria Maffeis
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy
| | - Rocco Cappellesso
- Pathological Anatomy Unit, Padova University Hospital, Padova, Italy
| | - Lorenzo Nicolè
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy
| | - Vincenza Guzzardo
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy
| | - Chiara Menin
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padova, Italy
| | - Lisa Elefanti
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, Padova, Italy
| | - Francesca Schiavi
- Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IOV-IRCCS, Padova, Italy
| | - Maria Guido
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy
| | - Ambrogio Fassina
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padova, Via Aristide Gabelli, 61, 35121, Padova, Italy.
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Yue H, Meng FX, Qian J, Xu BB, Li G, Wu JH. Calpastatin participates in the regulation of cell migration in BAP1-deficient uveal melanoma cells. Int J Ophthalmol 2019; 12:1680-1687. [PMID: 31741854 DOI: 10.18240/ijo.2019.11.03] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 06/12/2019] [Indexed: 12/11/2022] Open
Abstract
AIM To detect how BRCA-associated protein 1 (BAP1) regulates cell migration in uveal melanoma (UM) cells. METHODS Wound healing and transwell assays were performed to detect UM cell migration abilities. Protein chip, immunoprecipitations and surface plasmon resonance analyses were applied to identify BAP1 protein partners. Western blot and calpain activity assays were used to test the expression and function of calpastatin (CAST). RESULTS CAST protein was confirmed as a new BAP1 protein partner, and loss of BAP1 reduced the expression and function of CAST in UM cells. The overexpression of CAST rescued the cell migration phenotype caused by BAP1 loss. CONCLUSION BAP1 interacts with CAST in UM cells, and CAST and its subsequent calpain pathway may mediate BAP1-related cell migration regulation.
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Affiliation(s)
- Han Yue
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China
| | - Feng-Xi Meng
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China
| | - Jiang Qian
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China
| | - Bin-Bin Xu
- Department of Ophthalmology, Eye & ENT Hospital of Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China
| | - Gang Li
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China.,Experimental Research Center, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
| | - Ji-Hong Wu
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200433, China.,Experimental Research Center, Eye & ENT Hospital of Fudan University, Shanghai 200031, China
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Abstract
Renal cell carcinomas (RCCs) are a diverse set of malignancies that have recently been shown to harbour mutations in a number of chromatin modifier genes - including PBRM1, SETD2, BAP1, KDM5C, KDM6A, and MLL2 - through high-throughput sequencing efforts. Current research focuses on understanding the biological activities that chromatin modifiers employ to suppress tumorigenesis and on developing clinical approaches that take advantage of this knowledge. Unsurprisingly, several common themes unify the functions of these epigenetic modifiers, particularly regulation of histone post-translational modifications and nucleosome organization. Furthermore, chromatin modifiers also govern processes crucial for DNA repair and maintenance of genomic integrity as well as the regulation of splicing and other key processes. Many chromatin modifiers have additional non-canonical roles in cytoskeletal regulation, which further contribute to genomic stability, expanding the repertoire of functions that might be essential in tumorigenesis. Our understanding of how mutations in chromatin modifiers contribute to tumorigenesis in RCC is improving but remains an area of intense investigation. Importantly, elucidating the activities of chromatin modifiers offers intriguing opportunities for the development of new therapeutic interventions in RCC.
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Affiliation(s)
- Aguirre A de Cubas
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - W Kimryn Rathmell
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.
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26
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Veronese N, Stubbs B, Koyanagi A, Vaona A, Demurtas J, Schofield P, Maggi S. Mitochondrial genetic haplogroups and cardiovascular diseases: Data from the Osteoarthritis Initiative. PLoS One 2019; 14:e0213656. [PMID: 30921349 PMCID: PMC6438497 DOI: 10.1371/journal.pone.0213656] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 02/26/2019] [Indexed: 12/13/2022] Open
Abstract
Background Some case-control studies reported that mitochondrial haplogroups could be associated with the onset of cardiovascular diseases (CVD), but the literature regarding this topic is limited. We aimed to investigate whether any mitochondrial haplogroup carried a higher or lower risk of CVD in a large cohort of North American people affected by knee osteoarthritis or at high risk for this condition. Materials and methods A longitudinal cohort study including individuals from the Osteoarthritis Initiative was done. Haplogroups were assigned through a combination of sequencing and PCR-RFLP techniques. All the mitochondrial haplogroups have been named following this nomenclature: HV, JT, UK, IWX, and superHV/others. The strength of the association between mitochondrial haplogroups and incident CVD was evaluated through a Cox’s regression analysis, adjusted for potential confounders, and reported as hazard ratios (HRs) with their 95% confidence intervals (CIs). Results Overall, 3,288 Caucasian participants (56.8% women) with a mean age of 61.3±9.2 years without CVD at baseline were included. During a median follow-up of 8 years, 322 individuals (= 9.8% of baseline population) developed a CVD. After adjusting for 11 potential confounders at baseline and taking those with the HV haplotype as reference (the most frequent), those with JT carried a significant lower risk of CVD (HR = 0.75; 95%CI: 0.54–0.96; p = 0.03). Participants with the J haplogroup had the lowest risk of CVD (HR = 0.71; 95%CI: 0.46–0.95; p = 0.02). Conclusions The presence of JT haplogroups (particularly J) may be associated with a reduced risk of CVD. However, this result was not based on a high level of statistical significance. Thus, future research with larger sample size is needed to assess whether our results can be corroborated.
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Affiliation(s)
- Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Castellana Grotte (Ba), Italy
- * E-mail:
| | - Brendon Stubbs
- South London and Maudsley NHS Foundation Trust, Denmark Hill, London, United Kingdom
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, CIBERSAM, Sant Boi de Llobregat, Barcelona, Spain
| | - Alberto Vaona
- Primary Care Department, Azienda ULSS20 Verona, Verona, Italy
| | - Jacopo Demurtas
- Primary Care Department, Azienda USL Toscana Sud Est, Grosseto, Italy
| | - Patricia Schofield
- Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, United Kingdom
| | - Stefania Maggi
- National Research Council, Neuroscience Institute, Aging Branch, Padova, National Institute of Gastroenterology “S. De Bellis” Research Hospital, Castellana Grotte (Ba), Italy
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27
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Aydin AM, Singla N, Panwar V, Woldu SL, Freifeld Y, Wood CG, Karam JA, Weizer AZ, Raman JD, Remzi M, Rioux-Leclercq N, Haitel A, Roscigno M, Bolenz C, Bensalah K, Westerman ME, Sagalowsky AI, Shariat SF, Lotan Y, Bagrodia A, Kapur P, Margulis V, Krabbe LM. Prognostic significance of BAP1 expression in high-grade upper tract urothelial carcinoma: a multi-institutional study. World J Urol 2019; 37:2419-2427. [DOI: 10.1007/s00345-019-02678-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 02/06/2019] [Indexed: 01/21/2023] Open
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DICER1 mutations are frequent in müllerian adenosarcomas and are independent of rhabdomyosarcomatous differentiation. Mod Pathol 2019; 32:280-289. [PMID: 30266945 DOI: 10.1038/s41379-018-0132-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 07/13/2018] [Accepted: 07/14/2018] [Indexed: 12/30/2022]
Abstract
Müllerian adenosarcomas are biphasic epithelial-mesenchymal tumors with benign epithelial and malignant mesenchymal components. The sarcoma component may be low or high grade; the latter is often seen in the presence of stromal overgrowth, which correlates with worse clinical outcome. Heterologous differentiation may also occur, usually in association with stromal overgrowth. DICER1 mutations have been reported primarily in a small subset of adenosarcomas with rhabdomyosarcomatous elements, but whether these are specific to the rhabdomyosarcomatous phenotype is unclear. In this study, we examined the clinical, pathologic, and genomic features of 19 müllerian adenosarcomas enriched for tumors with rhabdomyosarcomatous differentiation, as well as eight uterine carcinosarcomas with a rhabdomyosarcoma component. Somatic hotspot mutations in the RNase IIIb domain of DICER1 were identified in 8/19 (42%) adenosarcomas, of which four showed rhabdomyosarcomatous differentiation. DICER1 mutations were detected in 4/6 (67%) cases with a rhabdomyosarcoma component and in 4/11 (36%) cases without rhabdomyosarcoma. At least two DICER1 mutations were identified in 7/8 (88%) tumors, of which four had a truncating mutation. The hotspot DICER1 mutation in the remaining tumor was hemizygous and associated with loss of heterozygosity. Other less frequent recurrent somatic pathogenic alterations included Ras or PI3K/PTEN pathway aberrations (5/19 each, 26%), CDK4/MDM2 amplifications (3/19, 16%), and mutations in TP53 (3/19) and ARID1A (3/19). Two tumors demonstrated homozygous BAP1 deletion. One tumor harbored an ESR1-NCOA3 fusion gene. Carcinosarcomas with rhabdomyosarcomatous differentiation showed frequent mutations in TP53 (7/8, 88%) and the PI3K/PTEN pathway (6/8, 75%) but lacked DICER1 mutations. The findings highlight the importance of DICER1 mutations in müllerian adenosarcoma tumorigenesis and show that these alterations are not exclusive to heterologous rhabdomyosarcomatous differentiation.
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Hmeljak J, Sanchez-Vega F, Hoadley KA, Shih J, Stewart C, Heiman D, Tarpey P, Danilova L, Drill E, Gibb EA, Bowlby R, Kanchi R, Osmanbeyoglu HU, Sekido Y, Takeshita J, Newton Y, Graim K, Gupta M, Gay CM, Diao L, Gibbs DL, Thorsson V, Iype L, Kantheti H, Severson DT, Ravegnini G, Desmeules P, Jungbluth AA, Travis WD, Dacic S, Chirieac LR, Galateau-Sallé F, Fujimoto J, Husain AN, Silveira HC, Rusch VW, Rintoul RC, Pass H, Kindler H, Zauderer MG, Kwiatkowski DJ, Bueno R, Tsao AS, Creaney J, Lichtenberg T, Leraas K, Bowen J, Felau I, Zenklusen JC, Akbani R, Cherniack AD, Byers LA, Noble MS, Fletcher JA, Robertson AG, Shen R, Aburatani H, Robinson BW, Campbell P, Ladanyi M. Integrative Molecular Characterization of Malignant Pleural Mesothelioma. Cancer Discov 2018; 8:1548-1565. [PMID: 30322867 PMCID: PMC6310008 DOI: 10.1158/2159-8290.cd-18-0804] [Citation(s) in RCA: 438] [Impact Index Per Article: 62.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 09/06/2018] [Accepted: 10/10/2018] [Indexed: 01/26/2023]
Abstract
Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.
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Affiliation(s)
- Julija Hmeljak
- Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Francisco Sanchez-Vega
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Katherine A Hoadley
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Juliann Shih
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Chip Stewart
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - David Heiman
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Patrick Tarpey
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Ludmila Danilova
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland
| | - Esther Drill
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ewan A Gibb
- GenomeDx Biosciences, Vancouver, British Columbia, Canada
| | - Reanne Bowlby
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Rupa Kanchi
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hatice U Osmanbeyoglu
- Computational Systems Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yoshitaka Sekido
- Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan
| | | | - Yulia Newton
- Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California
| | - Kiley Graim
- Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, California
| | - Manaswi Gupta
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Carl M Gay
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lixia Diao
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | | | - Lisa Iype
- Institute for Systems Biology, Seattle, Washington
| | | | - David T Severson
- Division of Thoracic Surgery, The Lung Center and International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Patrice Desmeules
- Department of Pathology, Quebec Heart and Lung Institute, Quebec, Canada
| | - Achim A Jungbluth
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William D Travis
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sanja Dacic
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Lucian R Chirieac
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | | | - Junya Fujimoto
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aliya N Husain
- Department of Pathology, University of Chicago, Chicago, Illinois
| | - Henrique C Silveira
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Sao Paulo, Brazil
| | - Valerie W Rusch
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Harvey Pass
- Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, New York
| | - Hedy Kindler
- Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, Illinois
| | - Marjorie G Zauderer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David J Kwiatkowski
- Division of Pulmonary Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Raphael Bueno
- Division of Thoracic Surgery, The Lung Center and International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts
| | - Anne S Tsao
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jenette Creaney
- School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia
| | - Tara Lichtenberg
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
| | - Kristen Leraas
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
| | - Jay Bowen
- The Research Institute at Nationwide Children's Hospital, Columbus, Ohio
| | - Ina Felau
- National Cancer Institute, Bethesda, Maryland
| | | | - Rehan Akbani
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrew D Cherniack
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Lauren A Byers
- Division of Thoracic Surgery, The Lung Center and International Mesothelioma Program, Brigham and Women's Hospital, Boston, Massachusetts
| | - Michael S Noble
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Jonathan A Fletcher
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - A Gordon Robertson
- Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
| | - Ronglai Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Bruce W Robinson
- School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia
| | - Peter Campbell
- Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK
| | - Marc Ladanyi
- Department of Pathology and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Patrone S, Maric I, Rutigliani M, Lanza F, Puntoni M, Banelli B, Rancati S, Angelini G, Amaro A, Ligorio P, Defferrari C, Castagnetta M, Bandelloni R, Mosci C, DeCensi A, Romani M, Pfeffer U, Viaggi S, Coviello DA. Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma. Genes Chromosomes Cancer 2018; 57:387-400. [PMID: 29689622 DOI: 10.1002/gcc.22541] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 04/06/2018] [Accepted: 04/09/2018] [Indexed: 12/27/2022] Open
Abstract
Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.
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Affiliation(s)
- Serena Patrone
- Department of Internal Medicine (DIMI), University of Genoa, Genova, Italy
| | - Irena Maric
- Department of Earth Sciences, Environment, and Life (DISTAV), University of Genoa, Genova, Italy.,Department of Biotherapy, Ospedale Policlinico San Martino, Genova, Italy
| | | | - Francesco Lanza
- Department of Ocular Oncology Unit, E.O. Ospedali Galliera, Genova, Italy
| | - Matteo Puntoni
- Department of Clinical Trial Unit/Scientific Direction, E.O. Ospedali Galliera, Genova, Italy
| | - Barbara Banelli
- Department of Tumor Epigenetics Unit, Ospedale Policlinico San Martino, Genova, Italy.,Department of Health Sciences, University of Genoa, Genova, Italy
| | - Silvia Rancati
- Department of Earth Sciences, Environment, and Life (DISTAV), University of Genoa, Genova, Italy
| | - Giovanna Angelini
- Department of Molecular Pathology Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Adriana Amaro
- Department of Molecular Pathology Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Paolo Ligorio
- Department of Ocular Oncology Unit, E.O. Ospedali Galliera, Genova, Italy
| | | | - Mauro Castagnetta
- Department of Human Genetics Laboratory, E.O. Ospedali Galliera, Genova, Italy
| | | | - Carlo Mosci
- Department of Ocular Oncology Unit, E.O. Ospedali Galliera, Genova, Italy
| | - Andrea DeCensi
- Department of Medical Oncology Unit, E.O. Ospedali Galliera, Genova, Italy
| | - Massimo Romani
- Department of Tumor Epigenetics Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Urlich Pfeffer
- Department of Molecular Pathology Unit, Ospedale Policlinico San Martino, Genova, Italy
| | - Silvia Viaggi
- Department of Earth Sciences, Environment, and Life (DISTAV), University of Genoa, Genova, Italy.,Department of Human Genetics Laboratory, E.O. Ospedali Galliera, Genova, Italy
| | - Domenico A Coviello
- Department of Human Genetics Laboratory, E.O. Ospedali Galliera, Genova, Italy
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31
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Riva G, Pea A, Pilati C, Fiadone G, Lawlor RT, Scarpa A, Luchini C. Histo-molecular oncogenesis of pancreatic cancer: From precancerous lesions to invasive ductal adenocarcinoma. World J Gastrointest Oncol 2018; 10:317-327. [PMID: 30364837 PMCID: PMC6198304 DOI: 10.4251/wjgo.v10.i10.317] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/13/2018] [Accepted: 08/12/2018] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a lethal malignancy, whose precursor lesions are pancreatic intraepithelial neoplasm, intraductal papillary mucinous neoplasm, intraductal tubulopapillary neoplasm, and mucinous cystic neoplasm. To better understand the biology of pancreatic cancer, it is fundamental to know its precursors and to study the mechanisms of carcinogenesis. Each of these precursors displays peculiar histological features, as well as specific molecular alterations. Starting from such pre-invasive lesions, this review aims at summarizing the most important aspects of carcinogenesis of pancreatic cancer, with a specific focus on the recent advances and the future perspectives of the research on this lethal tumor type.
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Affiliation(s)
- Giulio Riva
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Antonio Pea
- Department of Surgery, University and Hospital trust of Verona, Verona 37134, Italy
| | - Camilla Pilati
- Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, Paris 75006, France
| | - Giulia Fiadone
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Rita Teresa Lawlor
- ARC-Net Research Center, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy
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32
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Chen XX, Yin Y, Cheng JW, Huang A, Hu B, Zhang X, Sun YF, Wang J, Wang YP, Ji Y, Qiu SJ, Fan J, Zhou J, Yang XR. BAP1 acts as a tumor suppressor in intrahepatic cholangiocarcinoma by modulating the ERK1/2 and JNK/c-Jun pathways. Cell Death Dis 2018; 9:1036. [PMID: 30305612 PMCID: PMC6179995 DOI: 10.1038/s41419-018-1087-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 12/15/2022]
Abstract
Current therapeutic options for intrahepatic cholangiocarcinoma (ICC) are very limited, which is largely attributed to poor understanding of molecular pathogenesis of ICC. Breast cancer type 1 susceptibility protein-associated protein-1 (BAP1) has been reported to be a broad-spectrum tumor suppressor in many tumor types, yet its role in ICC remains unknown. The aim of this study was to investigate the clinical implications and biological function of BAP1 in ICC. Our results showed that the messenger RNA and protein levels of BAP1 were significantly downregulated in ICC versus paired non-tumor tissues. Overexpression of wild-type but not mutant BAP1 significantly suppressed ICC cell proliferation, cell cycle progression, and invasion in vitro, as well as tumor progression in vivo. Conversely, knockdown of BAP1 yielded opposing effects. Mechanistically, BAP1 functioned as a tumor suppressor in ICC by inhibiting the extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase/c-Jun pathways, and this function was abolished by inactivating mutations. Clinically, low BAP1 expression was positively correlated with aggressive tumor characteristics, such as larger tumor size, presence of lymphatic metastasis, and advanced tumor node metastasis stage. Survival analysis revealed that low BAP1 expression was significantly and independently associated with poor overall survival and relapse-free survival after curative surgery. In conclusion, BAP1 is a putative tumor suppressor of ICC, and may serve as a valuable prognostic biomarker as well as potential therapeutic target for ICC.
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Affiliation(s)
- Xu-Xiao Chen
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Yue Yin
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Jian-Wen Cheng
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Ao Huang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Bo Hu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Xin Zhang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Yun-Fan Sun
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Jian Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Yu-Peng Wang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Yuan Ji
- Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Department of Pathology, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
| | - Shuang-Jian Qiu
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China
| | - Xin-Rong Yang
- Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, 200032, Shanghai, China.
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Felley-Bosco E, MacFarlane M. Asbestos: Modern Insights for Toxicology in the Era of Engineered Nanomaterials. Chem Res Toxicol 2018; 31:994-1008. [PMID: 30156102 DOI: 10.1021/acs.chemrestox.8b00146] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Asbestos fibers are naturally occurring silicates that have been extensively used in the past, including house construction, but because of their toxicity, their use has been banned in 63 countries. Despite this, more than one million metric tons of asbestos are still consumed annually in countries where asbestos use has not been banned. Asbestos-related disease incidence is still increasing in several countries, including those countries that banned the use of asbestos more than 30 years ago. We highlight here recent knowledge obtained in experimental models about the mechanisms leading to tumor development following asbestos exposure, including genetic and epigenetic changes. Importantly, the landscape of alterations observed experimentally in tumor samples is consistent with alterations observed in clinical tumor samples; therefore, studies performed on early/precancer stages should help inform secondary prevention, which remains crucial in the absence of an efficient primary prevention. Knowledge gathered on asbestos should also help address future challenges, especially in view of the increased production of new materials that may behave similarly to asbestos fibers.
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Affiliation(s)
- Emanuela Felley-Bosco
- Laboratory of Molecular Oncology , University Hospital Zurich , Sternwartstrasse 14 , 8091 Zürich , Switzerland
| | - Marion MacFarlane
- MRC Toxicology Unit , University of Cambridge , Hodgkin Building, Leicester LE1 9HN , United Kingdom
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34
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Luchini C, Nottegar A, Vaona A, Stubbs B, Demurtas J, Maggi S, Veronese N. Female-specific association among I, J and K mitochondrial genetic haplogroups and cancer: A longitudinal cohort study. Cancer Genet 2018; 224-225:29-36. [PMID: 29778233 PMCID: PMC5973548 DOI: 10.1016/j.cancergen.2018.04.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 04/03/2018] [Indexed: 02/07/2023]
Abstract
Recent studies highlighted the role of mitochondrial dysregulation in cancer, suggesting that the different mitochondrial haplogroups might play a role in tumorigenesis and risk of cancer development. Our aim is to investigate whether any mitochondrial haplogroups carried a significant higher risk of cancer development in a large prospective cohort of North American people. The haplogroup assignment was performed by a combination of sequencing and PCR-RFLP techniques. Our specific outcome of interest was the incidence of any cancer during follow-up period. Overall, 3222 participants were included in the analysis. Women having I, J, K haplogroup reported a significant higher incidence of cancer compared to people with other haplogroups (p < 0.0001), whilst in men non association was found. In the multivariate analysis, women having I, J, K mitochondrial haplogroup reported a 50% increased risk of cancer (HR = 1.50; 95%CI: 1.04-2.16; p = 0.03). This gender-linked association may be partly explained by the role of mitochondrial function in female-specific (e.g. BRCA-driven) oncogenesis, but further studies are needed to better understand this potential correlation. Our findings may have important implications for cancer epidemiology and prevention.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134 Verona, Italy.
| | - Alessia Nottegar
- Department of Surgery, Section of Anatomical Pathology, San Bortolo Hospital, Vicenza, Italy
| | - Alberto Vaona
- Primary Care Department, Azienda ULSS20 Verona, Verona, Italy
| | - Brendon Stubbs
- South London and Maudsley NHS FoundationTrust, Denmark Hill, London SE5 8AZ, United Kingdom; Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8 AF, United Kingdom; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, United Kingdom
| | - Jacopo Demurtas
- Primary Care Department, Azienda USL Toscana Sud Est, Grosseto, Italy
| | - Stefania Maggi
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
| | - Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy; Institute for clinical Research and Education in Medicine (IREM), Padova, Italy
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35
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Fang Y, Shen X. Ubiquitin carboxyl-terminal hydrolases: involvement in cancer progression and clinical implications. Cancer Metastasis Rev 2018; 36:669-682. [PMID: 29080080 DOI: 10.1007/s10555-017-9702-0] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Protein ubiquitination and deubiquitination participate in a number of biological processes, including cell growth, differentiation, transcriptional regulation, and oncogenesis. Ubiquitin C-terminal hydrolases (UCHs), a subfamily of deubiquitinating enzymes (DUBs), includes four members: UCH-L1/PGP9.5 (protein gene product 9.5), UCH-L3, UCHL5/UCH37, and BRCA1-associated protein-1 (BAP1). Recently, more attention has been paid to the relationship between the UCH family and malignancies, which play different roles in the progression of different tumors. It remains controversial whether UCHL1 is a tumor promoter or suppressor. UCHL3 and UCH37 are considered to be tumor promoters, while BAP1 is considered to be a tumor suppressor. Studies have showed that UCH enzymes influence several signaling pathways that play crucial roles in oncogenesis, tumor invasion, and migration. In addition, UCH families are associated with tumor cell sensitivity to therapeutic modalities. Here, we reviewed the roles of UCH enzymes in the development of tumors, highlighting the potential consideration of UCH enzymes as new interesting targets for the development of anticancer drugs.
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Affiliation(s)
- Ying Fang
- The Department of Gastroenterology of Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China
| | - Xizhong Shen
- The Department of Gastroenterology of Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, People's Republic of China. .,Key Laboratory of Medical Molecule Virology, Ministry of Education and Health, Shanghai Institute of Liver Diseases Fudan University, Shanghai, 200032, People's Republic of China.
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36
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Veronese N, Solmi M, Caruso MG, Giannelli G, Osella AR, Evangelou E, Maggi S, Fontana L, Stubbs B, Tzoulaki I. Dietary fiber and health outcomes: an umbrella review of systematic reviews and meta-analyses. Am J Clin Nutr 2018; 107:436-444. [PMID: 29566200 DOI: 10.1093/ajcn/nqx082] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 12/22/2017] [Indexed: 12/12/2022] Open
Abstract
Background Several studies have suggested that higher consumption of dietary fiber is beneficial for a variety of health outcomes. However, many results have been inconclusive and, to our knowledge, there has been no attempt to systematically capture the breadth of outcomes associated with dietary fiber intake or to systematically assess the quality and the strength of the evidence on the associations of dietary fiber intake and different health outcomes or medical conditions. Objective The aim of this study was to describe the diverse health outcomes convincingly associated with dietary fiber consumption. Design This was an umbrella review of systematic reviews with meta-analysis of observational studies. For each association, random-effects summary effect size, 95% CIs, and 95% prediction intervals were estimated. We also assessed heterogeneity, evidence for small-study effect, and evidence for excess significance bias. We used these metrics to evaluate the credibility of the identified evidence. Results Our literature search identified 1351 abstracts. Of these, 18 meta-analyses including a total of 298 prospective observational studies and 21 outcomes were included. Outcomes studied included cancer and precancer lesions (n = 12), cardiovascular diseases (CVDs; n = 3), all-cause and specific-cause mortality (n = 4), type 2 diabetes (n = 1), and Crohn disease (n = 1). Overall, 6 (29%) of the 21 eligible outcomes reported highly significant summary results (P < 1 × 10-6); these included CVD and CVD mortality, coronary artery disease, pancreatic cancer, and gastric cancer. Overall, 3 of 21 (14%) outcomes presented convincing evidence (pancreatic cancer, CVD mortality, and all-cause mortality), but only CVD and all-cause mortality were based on prospective studies. Two other outcomes (10%), CVD and coronary artery disease, presented highly suggestive evidence based on prospective studies. Conclusion Our results support dietary recommendations that promote higher fiber intake as part of a healthy diet.
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Affiliation(s)
- Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology-Research Hospital, "Saverio de Bellis", Castellana Grotte, Italy
| | - Marco Solmi
- Department of Neurosciences, University of Padova, Padova, Italy
| | - Maria Gabriella Caruso
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology-Research Hospital, "Saverio de Bellis", Castellana Grotte, Italy
| | - Gianluigi Giannelli
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology-Research Hospital, "Saverio de Bellis", Castellana Grotte, Italy
| | - Alberto R Osella
- Ambulatory of Clinical Nutrition, National Institute of Gastroenterology-Research Hospital, "Saverio de Bellis", Castellana Grotte, Italy
| | - Evangelos Evangelou
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
- Department of Epidemiology and Biostatistics and MRC-PHE Center for Environment, School of Public Health, Imperial College London, London, United Kingdom
| | - Stefania Maggi
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
| | - Luigi Fontana
- Department of Clinical and Experimental Sciences, Brescia University Medical School, Brescia, Italy
- CEINGE Biotecnologie Avanzate, Naples, Italy
- Division of Geriatrics and Nutritional Science, Washington University, St. Louis, MO
| | - Brendon Stubbs
- Physiotherapy Department, South London and Maudsley National Health System Foundation Trust, London, United Kingdom
- Health Service and Population Research Department, Institute of Psychiatry, Psychology, and Neuroscience (IoPPN), King's College London, London, United Kingdom
- Faculty of Health, Social Care, and Education, Anglia Ruskin University, Chelmsford, United Kingdom
| | - Ioanna Tzoulaki
- Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece
- Department of Epidemiology and Biostatistics and MRC-PHE Center for Environment, School of Public Health, Imperial College London, London, United Kingdom
- Department of MRC-PHE Center for Environment, School of Public Health, Imperial College London, London, United Kingdom
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37
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Boffetta P, Righi L, Ciocan C, Pelucchi C, La Vecchia C, Romano C, Papotti M, Pira E. Validation of the diagnosis of mesothelioma and BAP1 protein expression in a cohort of asbestos textile workers from Northern Italy. Ann Oncol 2018; 29:484-489. [DOI: 10.1093/annonc/mdx762] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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38
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You HL, Huang WT, Liu TT, Weng SW, Eng HL. Mutations of candidate tumor suppressor genes at chromosome 3p in intrahepatic cholangiocarcinoma. Exp Mol Pathol 2017; 103:249-254. [PMID: 29122566 DOI: 10.1016/j.yexmp.2017.11.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 11/01/2017] [Indexed: 12/30/2022]
Abstract
The genetic status of candidate tumor suppressor genes (TSGs) at chromosome 3p has not yet been elucidated in intrahepatic cholangiocarcinoma (iCCA). Herein, we retrospectively investigated 32 fresh iCCA case samples from a single medical institution to clarify mutations of 11 TSGs by next-generation sequencing. Validation of the mutations was performed on the MassARRAY platform or by high-resolution melting curve analysis. We then integrated the gene mutations into copy number alterations at chromosome 3p that had been generated in a previous study using the same fresh iCCA samples, and correlated the integration results with the clinicopathologic features. Nine of the 32 (28.1%) iCCA patients had gene mutations at chromosome 3p, totaling 11 mutations across five genes. Those included five (15.6%) BAP1 mutations, two each (6.3%) of CACNA2D3 and RASSF1 mutations, and one each (3.1%) of ATG7 and PLCD1 mutations. Six (18.8%) cases had concurrent loss of chromosome 3p and gene mutations. Patients with TSG mutations had shorter disease-free and survival times than those without the mutations. Our data showed that iCCA patients with TSG mutations at chromosome 3p faced an adverse prognosis. BAP1 was the common target of mutational inactivation and may be a principal driver of 3p21 losses.
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Affiliation(s)
- Huey-Ling You
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Taiwan
| | - Wan-Ting Huang
- Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Taiwan.
| | - Ting-Ting Liu
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | | | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
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39
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Ghosh K, Modi B, James WD, Capell BC. BAP1: case report and insight into a novel tumor suppressor. BMC DERMATOLOGY 2017; 17:13. [PMID: 29166932 PMCID: PMC5700555 DOI: 10.1186/s12895-017-0065-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/15/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND BRCA1-Associated-Protein 1 (BAP1) is a dynamic tumor suppressor which, when mutated, has been associated with an increased risk of uveal melanoma, cutaneous melanoma, mesothelioma, and several other cancers. Germline BAP1 mutations have been extensively studied, where they have been found to cause hereditary cancer susceptibility. However, their sporadic counterparts, tumors that display a loss of BAP1 expression due to somatically arising mutations in the BAP1 gene, remain a poorly described entity. CASE PRESENTATION Here we present the case of a 49-year-old female who presented with an asymptomatic dome-shaped pink papule on the dorsal foot which was found on biopsy to be deficient in the BAP1 tumor suppressor. While the patient's family history did not suggest the presence of a familial cancer syndrome, germline genetic testing was performed and was negative. The patient underwent surgical excision of this sporadically appearing "BAPoma" by Mohs surgery. CONCLUSIONS Given the relatively banal clinical appearance of these dome-shaped neoplasms, sporadic BAPomas may often be overlooked by clinicians and dermatologists. In addition to providing a representative case, here we also provide a synopsis of the current understanding of these neoplasms, both in terms of the histopathological features, as well as the molecular mechanisms underlying BAP1 function and its ability to prevent tumorigenesis.
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Affiliation(s)
- Kanad Ghosh
- Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, USA
| | - Badri Modi
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, USA
| | - William D James
- Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, USA
| | - Brian C Capell
- Penn Epigenetics Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, USA. .,Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, 19104, USA. .,Biomedical Research Building 1007, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA.
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40
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Cozzi I, Oprescu FA, Rullo E, Ascoli V. Loss of BRCA1-associated protein 1 (BAP1) expression is useful in diagnostic cytopathology of malignant mesothelioma in effusions. Diagn Cytopathol 2017; 46:9-14. [DOI: 10.1002/dc.23837] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 07/20/2017] [Accepted: 09/27/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Ilaria Cozzi
- Department of Radiological, Oncological and Anatomo-Pathological Sciences; Sapienza University; Viale Regina, Rome 324-00161 Italy
| | - Florina Anca Oprescu
- Department of Radiological, Oncological and Anatomo-Pathological Sciences; Sapienza University; Viale Regina, Rome 324-00161 Italy
| | - Emma Rullo
- Department of Radiological, Oncological and Anatomo-Pathological Sciences; Sapienza University; Viale Regina, Rome 324-00161 Italy
| | - Valeria Ascoli
- Department of Radiological, Oncological and Anatomo-Pathological Sciences; Sapienza University; Viale Regina, Rome 324-00161 Italy
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Luchini C, Veronese N. Extranodal extension of nodal metastasis is the main prognostic moderator in squamous cell carcinoma of the esophagus after neoadjuvant chemoradiotherapy. J Thorac Dis 2017; 9:3609-3612. [PMID: 29268354 PMCID: PMC5723874 DOI: 10.21037/jtd.2017.09.36] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Accepted: 09/05/2017] [Indexed: 12/11/2022]
Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
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42
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Malignant Mesothelioma, BAP1 Immunohistochemistry, and VEGFA: Does BAP1 Have Potential for Early Diagnosis and Assessment of Prognosis? DISEASE MARKERS 2017; 2017:1310478. [PMID: 29085180 PMCID: PMC5612603 DOI: 10.1155/2017/1310478] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 08/22/2017] [Indexed: 11/26/2022]
Abstract
Malignant mesothelioma (MM) is an aggressive malignancy of the serosal membranes. Early diagnosis and accurate prognostication remain problematic. BAP1 is a tumour suppressor gene commonly mutated in MM. Germline BAP1 mutation has been associated with early onset and less aggressive disease compared with sporadic MM. Sporadic BAP1 mutations are common and are associated with improved survival in MM, contrary to other malignancies. This study investigated the prognostic role of BAP1 in matched cytology and surgical specimens and aimed to investigate the association between BAP1 and the established prognostic marker VEGFA from a cohort of 81 patients. BAP1 mutation was found in 58% of histology and 59% of cytology specimens. Loss of BAP1 expression in both surgical and cytology specimens was significantly associated with poorer survival in a multivariate analysis when controlling for known prognostic indicators. Increased levels of VEGFA in pleural effusions were associated with poor survival. We conclude that the prognostic significance of BAP1 mutations in MM cannot be determined in isolation of other prognostic factors, which may vary between patients. Pathologists should employ caution when commenting on prognostic implications of BAP1 status of MM patients in diagnostic pathology reports, but it may be useful for early diagnosis.
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Luchini C, Robertson SA, Hong SM, Felsenstein M, Anders RA, Pea A, Nottegar A, Veronese N, He J, Weiss MJ, Capelli P, Scarpa A, Argani P, Kapur P, Wood LD. PBRM1 loss is a late event during the development of cholangiocarcinoma. Histopathology 2017; 71:375-382. [PMID: 28394406 PMCID: PMC5552448 DOI: 10.1111/his.13234] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 04/06/2017] [Indexed: 12/20/2022]
Abstract
AIMS Somatic mutations in genes encoding chromatin remodellers have been reported recently in several cancer types, including approximately half of cholangiocarcinomas. One of the most commonly mutated chromatin remodellers in cholangiocarcinoma is the Polybromo-1 (PBRM1) gene located on chromosome 3p21, which encodes a subunit of the SWI/SNF complex. The aim of this study was to determine the timing of PBRM1 mutations in biliary carcinogenesis. METHODS AND RESULTS In order to accomplish this goal, we used immunohistochemistry to assess PBRM1 protein expression in a series of precursor lesions and invasive biliary carcinomas. Previous studies have correlated loss of protein expression on immunohistochemistry with inactivating mutations in this tumour suppressor gene. We found that PBRM1 loss occurred in approximately 26% of invasive cancers, but PBRM1 expression was retained in all biliary intra-epithelial neoplasia (BilIN) specimens, including 25 intrahepatic BilINs and 19 gallbladder BilINs. CONCLUSIONS These findings indicate that PBRM1 mutation (and resultant loss of expression) is a late event during biliary carcinogenesis. In addition, we confirm a lack of prognostic significance of PBRM1 status in invasive intrahepatic cholangiocarcinoma. This study provides important insights into the basic mechanisms of chromatin remodelling genes in carcinogenesis.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
| | - Scott A. Robertson
- Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
| | - Seung Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Robert A. Anders
- Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
| | - Antonio Pea
- Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
- Department of Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Alessia Nottegar
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy
- Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy
| | - Jin He
- Department of Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Matthew J. Weiss
- Department of Surgery, The Johns Hopkins University, Baltimore, MD, USA
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Pedram Argani
- Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
| | - Payal Kapur
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Laura D. Wood
- Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA
- The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University, Baltimore, MD, USA
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Serio G, Pezzuto F, Marzullo A, Scattone A, Cavone D, Punzi A, Fortarezza F, Gentile M, Buonadonna AL, Barbareschi M, Vimercati L. Peritoneal Mesothelioma with Residential Asbestos Exposure. Report of a Case with Long Survival (Seventeen Years) Analyzed by Cgh-Array. Int J Mol Sci 2017; 18:E1818. [PMID: 28829357 PMCID: PMC5578204 DOI: 10.3390/ijms18081818] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/17/2017] [Accepted: 08/18/2017] [Indexed: 12/18/2022] Open
Abstract
Malignant mesothelioma is a rare and aggressive tumor with limited therapeutic options. We report a case of a malignant peritoneal mesothelioma (MPM) epithelioid type, with environmental asbestos exposure, in a 36-year-old man, with a long survival (17 years). The patient received standard treatment which included cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS AND RESULTS Molecular analysis with comparative genomic hybridization (CGH)-array was performed on paraffin-embedded tumoral samples. Multiple chromosomal imbalances were detected. The gains were prevalent. Losses at 1q21, 2q11.1→q13, 8p23.1, 9p12→p11, 9q21.33→q33.1, 9q12→q21.33, and 17p12→p11.2 are observed. Chromosome band 3p21 (BAP1), 9p21 (CDKN2A) and 22q12 (NF2) are not affected. Conclusions: the defects observed in this case are uncommon in malignant peritoneal mesothelioma. Some chromosomal aberrations that appear to be random here, might actually be relevant events explaining the response to therapy, the long survival and, finally, may be considered useful prognostic factors in peritoneal malignant mesothelioma (PMM).
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Affiliation(s)
- Gabriella Serio
- Department of Emergency and Organ Transplantation, Division of Pathology, Medical School, University of Bari, 11 G. Cesare Square, 70124 Bari, Italy.
| | - Federica Pezzuto
- Department of Emergency and Organ Transplantation, Division of Pathology, Medical School, University of Bari, 11 G. Cesare Square, 70124 Bari, Italy.
| | - Andrea Marzullo
- Department of Emergency and Organ Transplantation, Division of Pathology, Medical School, University of Bari, 11 G. Cesare Square, 70124 Bari, Italy.
| | - Anna Scattone
- Division of Pathology, IRCCS, National Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Domenica Cavone
- Department of Interdisciplinary Medicine, Occupational Health Division, Medical School, University of Bari, 70124 Bari, Italy.
| | - Alessandra Punzi
- Department of Emergency and Organ Transplantation, Division of Pathology, Medical School, University of Bari, 11 G. Cesare Square, 70124 Bari, Italy.
| | - Francesco Fortarezza
- Department of Emergency and Organ Transplantation, Division of Pathology, Medical School, University of Bari, 11 G. Cesare Square, 70124 Bari, Italy.
| | - Mattia Gentile
- Division of Medical Genetics "Di Venere Hospital", 70124 Bari, Italy.
| | | | | | - Luigi Vimercati
- Department of Interdisciplinary Medicine, Occupational Health Division, Medical School, University of Bari, 70124 Bari, Italy.
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Hebert L, Bellanger D, Guillas C, Campagne A, Dingli F, Loew D, Fievet A, Jacquemin V, Popova T, Jean D, Mechta-Grigoriou F, Margueron R, Stern MH. Modulating BAP1 expression affects ROS homeostasis, cell motility and mitochondrial function. Oncotarget 2017; 8:72513-72527. [PMID: 29069806 PMCID: PMC5641149 DOI: 10.18632/oncotarget.19872] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Accepted: 07/23/2017] [Indexed: 12/30/2022] Open
Abstract
The tumor suppressor BAP1 associates with ASXL1/2 to form the core Polycomb complex PR-DUB, which catalyzes the removal of mono-ubiquitin from several substrates including histone H2A. This complex also mediates the poly-deubiquitination of HCFC1, OGT and PCG1-α, preventing them from proteasomal degradation. Surprisingly, considering its role in a Polycomb complex, no transcriptional signature was consistently found among BAP1-inactivated tumor types. It was hypothesized that BAP1 tumor suppressor activity could reside, at least in part, in stabilizing proteins through its poly-deubiquitinase activity. Quantitative mass spectrometry and gene expression arrays were used to investigate the consequences of BAP1 expression modulation in the NCI-H226 mesothelioma cell line. Analysis of differentially expressed proteins revealed enrichment in cytoskeleton organization, mitochondrial activity and ROS management, while gene expression analysis revealed enrichment in the epithelial-to-mesenchymal transition pathway. Functional assessments in BAP1 inactivated, BAP1 wild-type and BAP1 catalytically dead-expressing NCI-H226 and QR mesothelioma cell lines confirmed alteration of these pathways and demonstrated that BAP1 deubiquitinase activity was mandatory to maintain these phenotypes. Interestingly, monitoring intracellular ROS levels partly restored the morphology and the mitochondrial activity. Finally, the study suggests new tumorigenic and cellular functions of BAP1 and shows for the first time the interest of studying the proteome as readout of BAP1 inactivation.
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Affiliation(s)
- Lucie Hebert
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | - Dorine Bellanger
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | - Chloé Guillas
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | - Antoine Campagne
- Department of Developmental Biology and Genetics, CNRS UMR 3215/INSERM U934, Institut Curie, PSL Research University, Paris 75248, France
| | - Florent Dingli
- Mass Spectrometry and Proteomics facility, Institut Curie, PSL Research University, Paris 75248, France
| | - Damarys Loew
- Mass Spectrometry and Proteomics facility, Institut Curie, PSL Research University, Paris 75248, France
| | - Alice Fievet
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France.,Department of Genetics, Institut Curie, Paris 75248, France
| | - Virginie Jacquemin
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | - Tatiana Popova
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | | | - Fatima Mechta-Grigoriou
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France
| | - Raphaël Margueron
- Department of Developmental Biology and Genetics, CNRS UMR 3215/INSERM U934, Institut Curie, PSL Research University, Paris 75248, France
| | - Marc-Henri Stern
- Department of Genetics and Biology of Cancers, INSERM U830, Institut Curie, PSL Research University, Paris 75248, France.,Department of Genetics, Institut Curie, Paris 75248, France
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Veronese N, Stubbs B, Solmi M, Vaona A, Demurtas J, Carvalho AF, Koyanagi A, Thompson T, Zoratti M, Maggi S. Mitochondrial genetic haplogroups and depressive symptoms: A large study among people in North America. J Affect Disord 2017; 217:55-59. [PMID: 28391108 PMCID: PMC5482362 DOI: 10.1016/j.jad.2017.03.069] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/24/2017] [Accepted: 03/30/2017] [Indexed: 10/19/2022]
Abstract
BACKGROUND A possible relationship between mitochondrial haplogroups and psychiatric diseases (e.g. schizophrenia and bipolar disorder) has been postulated, but data regarding depression is still limited. We investigated whether any mitochondrial haplogroup carried a significant higher risk of depressive symptoms in a large prospective cohort of North American people included in the Osteoarthritis Initiative. METHODS Cross sectional data was derived from the Osteoarthritis Initiative. The haplogroup was assigned through a combination of sequencing and PCR-RFLP techniques. All the mitochondrial haplogroups were named following this nomenclature: H, U, K, J, T, V, SuperHV, I, W, X or Others. Depression was ascertained through the 20-item Center for Epidemiologic Studies-Depression (CES-D), with ≥16 indicating depressive symptoms. RESULTS Overall, 3601 Caucasian participants (55.9% women), mean age of 61.7±9.3 years were included. No difference was observed in mitochondrial haplogroups frequency among those with depressive symptoms (n=285, =7.9% of the baseline population) compared to participants with no depressive symptoms (N=3316) (chi-square test=0.53). Using a logistic regression analysis, adjusted for eight potential confounders, with those having the haplogroup H as the reference group (the most common haplogroup), no significant mitochondrial haplogroup was associated with prevalent depressive symptoms. The same results were evident in secondary analysis in which we matched depressed and non-depressed participants for age and sex. LIMITATIONS Cross-sectional design; only CES-D for evaluating mood; participants not totally representative of general population. CONCLUSIONS We found no evidence of any relationship between specific mitochondrial haplogroups and depressive symptoms. Future longitudinal research is required to confirm/ refute these findings.
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Affiliation(s)
- Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy; Institute for clinical Research and Education in Medicine (IREM), Padova, Italy.
| | - Brendon Stubbs
- South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AZ, United Kingdom; Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London SE5 8 AF, United Kingdom; Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, United Kingdom
| | - Marco Solmi
- Institute for clinical Research and Education in Medicine (IREM), Padova, Italy; Department of Neurosciences, University of Padova, Padova, Italy
| | - Alberto Vaona
- Primary Care Department, Azienda ULSS20 Verona, Verona, Italy
| | - Jacopo Demurtas
- Primary Care Department, Azienda USL Toscana Sud Est, Grosseto, Italy
| | - Andre F Carvalho
- Translational Psychiatry Research Group, Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Ai Koyanagi
- Research and Development Unit, Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, CIBERSAM, Barcelona, Spain
| | - Trevor Thompson
- Faculty of Education and Health, University of Greenwich, London, United Kingdom
| | - Mario Zoratti
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy; Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Stefania Maggi
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
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47
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Wang XY, Wang Z, Huang JB, Ren XD, Ye D, Zhu WW, Qin LX. Tissue-specific significance of BAP1 gene mutation in prognostic prediction and molecular taxonomy among different types of cancer. Tumour Biol 2017; 39:1010428317699111. [PMID: 28618948 DOI: 10.1177/1010428317699111] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BAP1 is an emerging tumor suppressor whose inactivating mutations have been found to play critical roles in tumor development. This study was conducted to elucidate the potential value of BAP1 mutation in guiding prognostic prediction and clinical stratification. We conducted a comprehensive analysis of relevant studies from multiple databases, to determine the impact of BAP1 mutation on the overall survival and disease-free survival of patients in various cancers. A total of 2457 patients from 21 studies were included in the final analysis. Although the pooled results demonstrated that BAP1 mutation was a negative indicator of overall survival (hazard ratio = 1.73; 95% confidence interval = 1.23-2.42) and disease-free survival (hazard ratio = 2.25; 95% confidence interval = 1.47-3.45), this prognostic value was only applicable to uveal melanoma and clear cell renal cell carcinoma, but not to malignant pleural mesothelioma or cholangiocarcinoma. Consistently, BAP1 mutation was correlated with critical clinicopathological features only in uveal melanoma and clear cell renal cell carcinoma. In uveal melanoma, BAP1 mutation and SF3B1/EIF1AX mutations were negatively correlated, and BAP1-mutant tumors indicated significant worse prognosis than SF3B1/EIF1AX-mutant tumors ( p = 0.028). While in clear cell renal cell carcinoma, BAP1 mutation was mutually exclusive with PBRM1 mutations, and BAP1-mutant clear cell renal cell carcinomas also showed significantly worse prognosis than PBRM1-mutant clear cell renal cell carcinomas ( p = 0.001). Our study revealed a unique tissue-specific significance of BAP1 mutation in prognostic prediction among different types of cancer. Clinically, combining detection of BAP1 mutation and other driver mutations may further allow for a more precise molecular taxonomy to stratify patients into distinct subgroups in uveal melanoma and clear cell renal cell carcinoma.
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Affiliation(s)
- Xiang-Yu Wang
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zheng Wang
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jian-Bo Huang
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Xu-Dong Ren
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Dan Ye
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,2 Molecular and Cell Biology Lab, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wen-Wei Zhu
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Lun-Xiu Qin
- 1 Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Loeser H, Waldschmidt D, Kuetting F, Schallenberg S, Zander T, Bollschweiler E, Hoelscher A, Weckermann K, Plum P, Alakus H, Buettner R, Quaas A. Somatic BRCA1-associated protein 1 (BAP1) loss is an early and rare event in esophageal adenocarcinoma. Mol Clin Oncol 2017; 7:225-228. [PMID: 28781790 DOI: 10.3892/mco.2017.1286] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 03/17/2017] [Indexed: 11/06/2022] Open
Abstract
Esophageal cancer is the eighth most common malignant tumor worldwide, and the number of incidences of esophageal adenocarcinoma is increasing in the Western world. Despite improvements in perioperative treatment, the overall survival rate of patients with esophageal adenocarcinoma remains poor. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is located on chromosome 3p21, and it is an enzyme with ubiquitin carboxyl hydrolase activity that regulates cell growth. It interacts with BRCA1, and the nuclear localization of BAP1 is required for its tumor suppressor function. BAP1 is frequently mutated in uveal melanomas, malignant mesothelioma and several carcinomas, including a subtype of renal cell carcinoma, intrahepatic cholangiocarcinoma and squamous cell carcinoma of the esophagus. Furthermore, several germline-associated mutations of tumors have been described (BAP1 hereditary cancer syndrome). However, the importance and frequency of BAP1 alterations in adenocarcinoma of the esophagus remain to be elucidated. In the present study, tissue microarrays of 332 resected adenocarcinomas (including a few cases of concomitant Barrett dysplasia) of the esophagus were constructed. The tumor tissue was analyzed using immunohistochemistry to investigate the levels of BAP1 expression. Fibroblasts or inflammatory cells served as an internal positive control. Three adenocarcinomas revealed nuclear loss of BAP1 (0.9%). One case with concomitant Barrett dysplasia also exhibited a loss of BAP1. Of the resected adenocarcinomas, 329 of them exhibited an intact and uniform strong nuclear staining pattern. To the best of our knowledge, this is the first description of BAP1 deficiency in adenocarcinomas of the esophagus. Furthermore, it has been demonstrated that BAP1 loss is possibly an early event in esophageal adenocarcinoma. These results warrant further functional and clinical evaluation.
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Affiliation(s)
- Heike Loeser
- Institute of Pathology, University of Cologne, D-50937 Cologne, Germany
| | - Dirk Waldschmidt
- Department of Gastrointestinal Diseases and Hepatology, University of Cologne, D-50937 Cologne, Germany
| | - Fabian Kuetting
- Department of Gastrointestinal Diseases and Hepatology, University of Cologne, D-50937 Cologne, Germany
| | | | - Thomas Zander
- Department of Oncology and Hematology, Center of Integrated Oncology, University of Cologne, Gastrointestinal Cancer Group Cologne (GCGC), D-50937 Cologne, Germany
| | - Elfriede Bollschweiler
- Department of Visceral Surgery, University of Cologne, Gastrointestinal Cancer Group Cologne (GCGC), D-50937 Cologne, Germany
| | - Arnulf Hoelscher
- Department of Visceral Surgery, University of Cologne, Gastrointestinal Cancer Group Cologne (GCGC), D-50937 Cologne, Germany
| | | | - Patrick Plum
- Department of Visceral Surgery, University of Cologne, Gastrointestinal Cancer Group Cologne (GCGC), D-50937 Cologne, Germany
| | - Hakan Alakus
- Department of Visceral Surgery, University of Cologne, Gastrointestinal Cancer Group Cologne (GCGC), D-50937 Cologne, Germany
| | - Reinhard Buettner
- Institute of Pathology, University of Cologne, D-50937 Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University of Cologne, D-50937 Cologne, Germany
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McLoughlin KC, Kaufman AS, Schrump DS. Targeting the epigenome in malignant pleural mesothelioma. Transl Lung Cancer Res 2017; 6:350-365. [PMID: 28713680 DOI: 10.21037/tlcr.2017.06.06] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Malignant pleural mesotheliomas (MPM) are notoriously refractory to conventional treatment modalities. Recent insights regarding epigenetic alterations in MPM provide the preclinical rationale for the evaluation of novel combinatorial regimens targeting the epigenome in these neoplasms.
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Affiliation(s)
- Kaitlin C McLoughlin
- Thoracic Epigenetics Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Andrew S Kaufman
- Thoracic Epigenetics Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - David S Schrump
- Thoracic Epigenetics Section, Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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50
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Luchini C, Fleischmann A, Boormans JL, Fassan M, Nottegar A, Lucato P, Stubbs B, Solmi M, Porcaro A, Veronese N, Brunelli M, Scarpa A, Cheng L. Extranodal extension of lymph node metastasis influences recurrence in prostate cancer: a systematic review and meta-analysis. Sci Rep 2017; 7:2374. [PMID: 28539662 PMCID: PMC5443831 DOI: 10.1038/s41598-017-02577-4] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 04/12/2017] [Indexed: 12/12/2022] Open
Abstract
The extranodal extension (ENE) of nodal metastasis involves the extension of neoplastic cells through the lymph node capsule into the perinodal adipose tissue. This morphological feature has recently been indicated as an important prognostic factor in various cancer types, but its role in prostate cancer is still unclear. We aimed to clarify it, performing the first meta-analysis on this issue, comparing prognostic parameters in surgically treated, node-positive prostate cancer patients with (ENE+) vs. without (ENE-) ENE. Data were summarized using risk ratios (RRs) for number of deaths/recurrences and hazard ratios (HRs), with 95% confidence intervals (CI), for the time-dependent risk related to ENE positivity. Six studies followed-up 1,113 patients with N1 prostate cancer (658 ENE+ vs. 455 ENE-) for a median of 83 months. The presence of ENE was associated with a significantly higher risk of biochemical recurrence (RR = 1.15; 95%CI: 1.03-1.28; I2 = 0%; HR = 1.40, 95%CI: 1.12-1.74; I2 = 0%) and "global" (biochemical recurrence and distant metastasis) recurrence (RR = 1.15; 95%CI: 1.04-1.28; I2 = 0%; HR = 1.41, 95%CI: 1.14-1.74; I2 = 0%). ENE emerged as a potential prognostic moderator, earmarking a subgroup of patients at higher risk of recurrence. It may be considered for the prognostic stratification of metastatic patients. New possible therapeutic approaches may explore more in depth this prognostic parameter.
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Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy.
- ARC-NET Research Center, University and Hospital Trust of Verona, Verona, Italy.
- Department of Pathology, Santa Chiara Hospital, Trento, Italy.
| | - Achim Fleischmann
- Institute of Pathology, University of Bern, CH-3010, Bern, Switzerland
| | - Joost L Boormans
- Department of Urology, Erasmus MC - Cancer Institute, Rotterdam, The Netherlands
| | - Matteo Fassan
- Department of Medicine, DIMED, University of Padua, Padua, Italy
| | - Alessia Nottegar
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Paola Lucato
- Department of Medicine, DIMED, University of Padua, Padua, Italy
| | - Brendon Stubbs
- Health Service and Population Research Department, King's College London, De Crespigny Park, London, SE5 8AF, United Kingdom
| | - Marco Solmi
- Department of Neuroscience, University of Padua, Padua, Italy
| | - Antonio Porcaro
- Urologic Clinic, University and Hospital trust of Verona, Verona, Italy
| | - Nicola Veronese
- National Research Council, Neuroscience Institute, Aging Branch, Padova, Italy
- Institute for clinical Research and Education in Medicine (IREM), Padova, Italy
| | - Matteo Brunelli
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Center, University and Hospital Trust of Verona, Verona, Italy
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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