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Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [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: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
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Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
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Thet M, Plazzer JP, Capella G, Latchford A, Nadeau EA, Greenblatt MS, Macrae F. Phenotype correlations with pathogenic DNA variants in the MUTYH gene. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.15.24307143. [PMID: 38798681 PMCID: PMC11118659 DOI: 10.1101/2024.05.15.24307143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
MUTYH -associated polyposis (MAP) is an autosomal recessive disorder where the inheritance of constitutional biallelic pathogenic MUTYH variants predisposes a person to the development of adenomas and colorectal cancer (CRC). It is also associated with extracolonic and extraintestinal manifestations that may overlap with the phenotype of familial adenomatous polyposis (FAP). Currently, there are discrepancies in the literature regarding whether certain phenotypes are truly associated with MAP. This narrative review aims to explore the phenotypic spectrum of MAP to better characterise the MAP phenotype. A literature search was conducted to identify articles reporting on MAP-specific phenotypes. Clinical data from 2109 MAP patients identified from the literature showed that 1123 patients (53.2%) had CRC. Some patients with CRC had no associated adenomas, suggesting that adenomas are not an obligatory component of MAP. Carriers of the two missense founder variants, and possibly truncating variants, had an increased cancer risk when compared to those who carry other pathogenic variants. It has been suggested that somatic G:C>T:A transversions are a mutational signature of MAP, and could be used as a biomarker in screening and identifying patients with atypical MAP, or in associating certain phenotypes with MAP. The extracolonic and extraintestinal manifestations that have been associated with MAP include duodenal adenomas, duodenal cancer, fundic gland polyps, gastric cancer, ovarian cancer, bladder cancer and skin cancer. The association of breast cancer and endometrial cancer with MAP remains disputed. Desmoids and Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPEs) are rarely reported in MAP, but have long been seen in FAP patients, and thus could act as a distinguishing feature between the two. This collection of MAP phenotypes will assist in the assessment of pathogenic MUTYH variants using the American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) Variant Interpretation Guidelines, and ultimately improve patient care.
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Cipri S, Del Baldo G, Carai A, Cacchione A, Agolini E, Novelli A, Rossi S, Colafati GS, Boccuto L, Mastronuzzi A. A second case report of medulloblastoma in a patient carrying biallelic pathogenic MUTYH germline variants. Neuropathol Appl Neurobiol 2024; 50:e12968. [PMID: 38477379 DOI: 10.1111/nan.12968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 02/15/2024] [Accepted: 02/20/2024] [Indexed: 03/14/2024]
Affiliation(s)
- Selene Cipri
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giada Del Baldo
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Andrea Carai
- Department of Neurosciences, Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Antonella Cacchione
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Emanuele Agolini
- Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Antonio Novelli
- Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Sabrina Rossi
- Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Giovanna Stefania Colafati
- Imaging Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Neuroscience, Imaging and Clinical Sciences (DNISC), University "Gabriele D'Annunzio" of Chieti-Pescara, Chieti, Italy
| | - Luigi Boccuto
- Healthcare Genetics Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, South Carolina, USA
| | - Angela Mastronuzzi
- Department of Hematology/Oncology, Cell Therapy, Gene Therapies and Hemopoietic Transplant, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Keske A, Weisman P, Ospina-Romero M, Raut P, Smith-Simmer K, Zakas AL, Flynn C, Xu J. Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers. Breast Cancer Res Treat 2024; 204:151-158. [PMID: 38062336 DOI: 10.1007/s10549-023-07173-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 11/02/2023] [Indexed: 01/24/2024]
Abstract
PURPOSE Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. METHODS The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. RESULTS Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. CONCLUSION Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.
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Affiliation(s)
- Aysenur Keske
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
| | - Paul Weisman
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Monica Ospina-Romero
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Prachi Raut
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Kelcy Smith-Simmer
- Master of Genetic Counselor Studies, Academic Affairs, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Oncology Genetics, University of Wisconsin Carbone Cancer Center, UW Health, Madison, WI, USA
| | - Anna L Zakas
- Master of Genetic Counselor Studies, Academic Affairs, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
- Oncology Genetics, University of Wisconsin Carbone Cancer Center, UW Health, Madison, WI, USA
| | - Christopher Flynn
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jin Xu
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
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Peña-López J, Jiménez-Bou D, Ruíz-Gutiérrez I, Martín-Montalvo G, Alameda-Guijarro M, Rueda-Lara A, Ruíz-Giménez L, Higuera-Gómez O, Gallego A, Pertejo-Fernández A, Sánchez-Cabrero D, Feliu J, Rodríguez-Salas N. Prevalence and Distribution of MUTYH Pathogenic Variants, Is There a Relation with an Increased Risk of Breast Cancer? Cancers (Basel) 2024; 16:315. [PMID: 38254803 PMCID: PMC10813893 DOI: 10.3390/cancers16020315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND MUTYH has been implicated in hereditary colonic polyposis and colorectal carcinoma. However, there are conflicting data refgarding its relationship to hereditary breast cancer. Therefore, we aimed to assess if MUTYH mutations contribute to breast cancer susceptibility. METHODS We retrospectively reviewed 3598 patients evaluated from June 2018 to June 2023 at the Hereditary Cancer Unit of La Paz University Hospital, focusing on those with detected MUTYH variants. RESULTS Variants of MUTYH were detected in 56 patients (1.6%, 95%CI: 1.2-2.0). Of the 766 patients with breast cancer, 14 patients were carriers of MUTYH mutations (1.8%, 95%CI: 0.5-3.0). The prevalence of MUTYH mutation was significantly higher in the subpopulation with colonic polyposis (11.3% vs. 1.1%, p < 0.00001, OR = 11.2, 95%CI: 6.2-22.3). However, there was no significant difference in the prevalence within the subpopulation with breast cancer (1.8% vs. 1.5%, p = 0.49, OR = 1.2, 95%CI: 0.7-2.3). CONCLUSION In our population, we could not establish a relationship between MUTYH and breast cancer. These findings highlight the necessity for a careful interpretation when assessing the role of MUTYH mutations in breast cancer risk.
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Affiliation(s)
- Jesús Peña-López
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Diego Jiménez-Bou
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Icíar Ruíz-Gutiérrez
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Gema Martín-Montalvo
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | | | - Antonio Rueda-Lara
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Leticia Ruíz-Giménez
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Oliver Higuera-Gómez
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Alejandro Gallego
- Department of Medical Oncology, Clínica Universidad de Navarra, 28027 Madrid, Spain
| | | | | | - Jaime Feliu
- Department of Medical Oncology, Hospital Universitario La Paz, 28046 Madrid, Spain
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Chakraborty B, Agarwal S, Kori S, Das R, Kashaw V, Iyer AK, Kashaw SK. Multiple Protein Biomarkers and Different Treatment Strategies for Colorectal Carcinoma: A Comprehensive Prospective. Curr Med Chem 2024; 31:3286-3326. [PMID: 37151060 DOI: 10.2174/0929867330666230505165031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 05/09/2023]
Abstract
In this review, we emphasized important biomarkers, pathogenesis, and newly developed therapeutic approaches in the treatment of colorectal cancer (CRC). This includes a complete description of small-molecule inhibitors, phytopharmaceuticals with antiproliferative potential, monoclonal antibodies for targeted therapy, vaccinations as immunotherapeutic agents, and many innovative strategies to intervene in the interaction of oncogenic proteins. Many factors combine to determine the clinical behavior of colorectal cancer and it is still difficult to comprehend the molecular causes of a person's vulnerability to CRC. It is also challenging to identify the causes of the tumor's onset, progression, and responsiveness or resistance to antitumor treatment. Current recommendations for targeted medications are being updated by guidelines throughout the world in light of the growing number of high-quality clinical studies. So, being concerned about the aforementioned aspects, we have tried to present a summarized pathogenic view, including a brief description of biomarkers and an update of compounds with their underlying mechanisms that are currently under various stages of clinical testing. This will help to identify gaps or shortfalls that can be addressed in upcoming colorectal cancer research.
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Affiliation(s)
- Biswadip Chakraborty
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivangi Agarwal
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Shivam Kori
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
| | - Ratnesh Das
- Department of Chemistry, ISF College of Pharmacy, Moga-Punjab, India
| | - Varsha Kashaw
- Sagar Institute of Pharmaceutical Sciences, Sagar (M.P.), India
| | - Arun K Iyer
- Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan, USA
- Molecular Imaging Program, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Sushil Kumar Kashaw
- Integrated Drug Discovery Research Laboratory, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar (MP), India
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Bilyalov A, Danishevich A, Nikolaev S, Vorobyov N, Abramov I, Pismennaya E, Terehova S, Kosilova Y, Primak A, Stanoevich U, Lisica T, Shipulin G, Gamayunov S, Kolesnikova E, Khatkov I, Gusev O, Bodunova N. Novel Pathogenic Variants in Hereditary Cancer Syndromes in a Highly Heterogeneous Cohort of Patients: Insights from Multigene Analysis. Cancers (Basel) 2023; 16:85. [PMID: 38201513 PMCID: PMC10778304 DOI: 10.3390/cancers16010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/21/2023] [Accepted: 12/22/2023] [Indexed: 01/12/2024] Open
Abstract
Cancer is a major global public health challenge, affecting both quality of life and mortality. Recent advances in genetic research have uncovered hereditary cancer syndromes (HCS) that predispose individuals to malignant neoplasms. While traditional single-gene testing has focused on high-penetrance genes, the past decade has seen a shift toward multigene panels, which facilitate the analysis of multiple genes associated with specific HCS. This approach reveals variants in less-studied gene regions and improves our understanding of cancer predisposition. In a study composed of Russian patients with clinical signs of HCS, we used a multigene hereditary cancer panel and revealed 21.6% individuals with pathogenic or likely pathogenic genetic variants. BRCA1/BRCA2 mutations predominated, followed by the CHEK2 and ATM variants. Of note, 16 previously undescribed variants were identified in the MUTYH, GALNT12, MSH2, MLH1, MLH3, EPCAM, and POLE genes. The implications of the study extend to personalized cancer prevention and treatment strategies, especially in populations lacking extensive epidemiological data, such as Russia. Overall, our research provides valuable genetic insights that give the way for further investigation and advances in the understanding and management of hereditary cancer syndromes.
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Affiliation(s)
- Airat Bilyalov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Anastasiia Danishevich
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Sergey Nikolaev
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Nikita Vorobyov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Ivan Abramov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
- The Federal State Budgetary Scientific Institution “Izmerov Research Institute of Occupational Health”, 105275 Moscow, Russia
| | | | - Svetlana Terehova
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Yuliya Kosilova
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Anastasiia Primak
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Uglesha Stanoevich
- Kursk Regional Scientific and Clinical Center Named after G. Y. Ostroverkhov, 305524 Kursk, Russia; (S.T.); (Y.K.); (A.P.)
| | - Tatyana Lisica
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical and Biological Agency, 119435 Moscow, Russia
| | - German Shipulin
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical and Biological Agency, 119435 Moscow, Russia
| | - Sergey Gamayunov
- Nizhny Novgorod Regional Oncologic Hospital, 603163 Nizhny Novgorod, Russia
| | - Elena Kolesnikova
- Nizhny Novgorod Regional Oncologic Hospital, 603163 Nizhny Novgorod, Russia
| | - Igor Khatkov
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
| | - Oleg Gusev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia
- Life Improvement by Future Technologies (LIFT) Center, 121205 Moscow, Russia
| | - Natalia Bodunova
- SBHI Moscow Clinical Scientific Center Named after Loginov MHD, 111123 Moscow, Russia (I.K.)
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Fahrer J, Wittmann S, Wolf AC, Kostka T. Heme Oxygenase-1 and Its Role in Colorectal Cancer. Antioxidants (Basel) 2023; 12:1989. [PMID: 38001842 PMCID: PMC10669411 DOI: 10.3390/antiox12111989] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Heme oxygenase-1 (HO-1) is an enzyme located at the endoplasmic reticulum, which is responsible for the degradation of cellular heme into ferrous iron, carbon monoxide and biliverdin-IXa. In addition to this main function, the enzyme is involved in many other homeostatic, toxic and cancer-related mechanisms. In this review, we first summarize the importance of HO-1 in physiology and pathophysiology with a focus on the digestive system. We then detail its structure and function, followed by a section on the regulatory mechanisms that control HO-1 expression and activity. Moreover, HO-2 as important further HO isoform is discussed, highlighting the similarities and differences with regard to HO-1. Subsequently, we describe the direct and indirect cytoprotective functions of HO-1 and its breakdown products carbon monoxide and biliverdin-IXa, but also highlight possible pro-inflammatory effects. Finally, we address the role of HO-1 in cancer with a particular focus on colorectal cancer. Here, relevant pathways and mechanisms are presented, through which HO-1 impacts tumor induction and tumor progression. These include oxidative stress and DNA damage, ferroptosis, cell cycle progression and apoptosis as well as migration, proliferation, and epithelial-mesenchymal transition.
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Affiliation(s)
- Jörg Fahrer
- Division of Food Chemistry and Toxicology, Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger Strasse 52, D-67663 Kaiserslautern, Germany; (S.W.); (A.-C.W.)
| | | | | | - Tina Kostka
- Division of Food Chemistry and Toxicology, Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger Strasse 52, D-67663 Kaiserslautern, Germany; (S.W.); (A.-C.W.)
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Lirussi L, Nilsen HL. DNA Glycosylases Define the Outcome of Endogenous Base Modifications. Int J Mol Sci 2023; 24:10307. [PMID: 37373453 DOI: 10.3390/ijms241210307] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Chemically modified nucleic acid bases are sources of genomic instability and mutations but may also regulate gene expression as epigenetic or epitranscriptomic modifications. Depending on the cellular context, they can have vastly diverse impacts on cells, from mutagenesis or cytotoxicity to changing cell fate by regulating chromatin organisation and gene expression. Identical chemical modifications exerting different functions pose a challenge for the cell's DNA repair machinery, as it needs to accurately distinguish between epigenetic marks and DNA damage to ensure proper repair and maintenance of (epi)genomic integrity. The specificity and selectivity of the recognition of these modified bases relies on DNA glycosylases, which acts as DNA damage, or more correctly, as modified bases sensors for the base excision repair (BER) pathway. Here, we will illustrate this duality by summarizing the role of uracil-DNA glycosylases, with particular attention to SMUG1, in the regulation of the epigenetic landscape as active regulators of gene expression and chromatin remodelling. We will also describe how epigenetic marks, with a special focus on 5-hydroxymethyluracil, can affect the damage susceptibility of nucleic acids and conversely how DNA damage can induce changes in the epigenetic landscape by altering the pattern of DNA methylation and chromatin structure.
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Affiliation(s)
- Lisa Lirussi
- Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
- Section of Clinical Molecular Biology (EpiGen), Akershus University Hospital, 1478 Lørenskog, Norway
- Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway
| | - Hilde Loge Nilsen
- Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway
- Department of Microbiology, Oslo University Hospital, 0424 Oslo, Norway
- Unit for Precision Medicine, Akershus University Hospital, 1478 Lørenskog, Norway
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10
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Exome sequencing identifies novel genes and variants in patients with Hirschsprung disease. J Pediatr Surg 2023; 58:723-728. [PMID: 36586783 DOI: 10.1016/j.jpedsurg.2022.11.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 11/09/2022] [Accepted: 11/16/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Hirschsprung disease (HSCR) is a complex genetic disease characterized by the absence of ganglion cells in the intestines, leading to a functional obstruction in infants. At least 24 genes have been identified for the pathogenesis of HSCR. They contributed to approximately 72% of HSCR cases. We aimed to elucidate further the genetic basis of HSCR in Indonesia using the whole-exome sequencing (WES) approach. METHODS WES was performed in 39 sporadic non-syndromic HSCR patients and 16 non-HSCR subjects as controls. Variants presented in controls were excluded, followed by in silico prediction tools and population allele frequency databases to select rare variants. We determined the minor allele frequency (MAF) using gnomAD (MAF <0.1%). RESULTS We involved 24 (61.5%) males and 15 (38.5%) females. Most patients (62%) had short-segment aganglionosis and underwent the Duhamel procedure (41%). We identified several candidate novel variants in HSCR-related genes, including UBR4, GDNF, and ECE1. Moreover, we also identified some novel candidate genes, including a possible compound heterozygous variant in the MUTYH gene: the first variant, a known protein-truncating variant associated with colorectal cancer (CRC), p.Glu452Ter and the second variant is novel, p.Ala39Val. Moreover, the type of variants was not associated with the aganglionosis type. CONCLUSIONS We identified several novel genes and variants, including the variant associated with CRC, that might contribute to the pathogenesis of HSCR. No genotype-phenotype associations were noted. Our study further confirms the complex network involved in enteric nervous system development and HSCR pathogenesis. LEVEL OF EVIDENCE Level III.
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11
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Bai P, Fan T, Sun G, Wang X, Zhao L, Zhong R. The dual role of DNA repair protein MGMT in cancer prevention and treatment. DNA Repair (Amst) 2023; 123:103449. [PMID: 36680944 DOI: 10.1016/j.dnarep.2023.103449] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/21/2022] [Accepted: 01/09/2023] [Indexed: 01/15/2023]
Abstract
Alkylating agents are genotoxic chemicals that can induce and treat various types of cancer. This occurs through covalent bonding with cellular macromolecules, in particular DNA, leading to the loss of functional integrity under the persistence of modifications upon replication. O6-alkylguanine (O6-AlkylG) adducts are proposed to be the most potent DNA lesions induced by alkylating agents. If not repaired correctly, these adducts can result, at the molecular level, in DNA point mutations, chromosome aberrations, recombination, crosslinking, and single- and double-strand breaks (SSB/DSBs). At the cellular level, these lesions can result in malignant transformation, senescence, or cell death. O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein capable of removing the alkyl groups from O6-AlkylG adducts in a damage reversal process that can prevent the adverse biological effects of DNA damage caused by guanine O6-alkylation. MGMT can thereby defend normal cells against tumor initiation, however it can also protect tumor cells against the beneficial effects of chemotherapy. Hence, MGMT can play an important role in both the prevention and treatment of cancer; thus, it can be considered as a double-edged sword. From a clinical perspective, MGMT is a therapeutic target, and it is important to explore the rational development of its clinical exploitation.
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Affiliation(s)
- Peiying Bai
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Tengjiao Fan
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China; Department of Medical Technology, Beijing Pharmaceutical University of Staff and Workers, Beijing 100079, China
| | - Guohui Sun
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.
| | - Xin Wang
- Department of Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100029, China
| | - Lijiao Zhao
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
| | - Rugang Zhong
- Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China
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12
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Chen L, Ye L, Hu B. Hereditary Colorectal Cancer Syndromes: Molecular Genetics and Precision Medicine. Biomedicines 2022; 10:biomedicines10123207. [PMID: 36551963 PMCID: PMC9776295 DOI: 10.3390/biomedicines10123207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/28/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Hereditary CRC syndromes account for approximately 5-10% of all CRC, with a lifetime risk of CRC that approaches 50-80% in the absence of endoscopic or surgical treatment. Hereditary CRC syndromes can be phenotypically divided into polyposis and non-polyposis syndrome, mainly according to the conditions of polyps. The typical representatives are familial adenomatous polyposis (FAP) and Lynch syndromes (LS), respectively. Over the past few decades, molecular genetics enhanced the discovery of cancer-predisposing genes and revolutionized the field of clinical oncology. Hereditary CRC syndromes have been a key part of this effort, with data showing that pathogenic variants are present in up to 10% of cases. Molecular phenotypes of tumors can not only help identify individuals with genetic susceptibility to CRC but also guide the precision prevention and treatment for the development of CRC. This review emphasizes the molecular basis and prevention strategies for hereditary CRC syndromes.
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Affiliation(s)
| | | | - Bing Hu
- Correspondence: ; Tel.: +86-18980601278
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13
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Hahm JY, Park J, Jang ES, Chi SW. 8-Oxoguanine: from oxidative damage to epigenetic and epitranscriptional modification. Exp Mol Med 2022; 54:1626-1642. [PMID: 36266447 PMCID: PMC9636213 DOI: 10.1038/s12276-022-00822-z] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/06/2022] [Accepted: 05/26/2022] [Indexed: 12/29/2022] Open
Abstract
In pathophysiology, reactive oxygen species control diverse cellular phenotypes by oxidizing biomolecules. Among these, the guanine base in nucleic acids is the most vulnerable to producing 8-oxoguanine, which can pair with adenine. Because of this feature, 8-oxoguanine in DNA (8-oxo-dG) induces a G > T (C > A) mutation in cancers, which can be deleterious and thus actively repaired by DNA repair pathways. 8-Oxoguanine in RNA (o8G) causes problems in aberrant quality and translational fidelity, thereby it is subjected to the RNA decay pathway. In addition to oxidative damage, 8-oxo-dG serves as an epigenetic modification that affects transcriptional regulatory elements and other epigenetic modifications. With the ability of o8G•A in base pairing, o8G alters structural and functional RNA-RNA interactions, enabling redirection of posttranscriptional regulation. Here, we address the production, regulation, and function of 8-oxo-dG and o8G under oxidative stress. Primarily, we focus on the epigenetic and epitranscriptional roles of 8-oxoguanine, which highlights the significance of oxidative modification in redox-mediated control of gene expression.
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Affiliation(s)
- Ja Young Hahm
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Jongyeun Park
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Eun-Sook Jang
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea
| | - Sung Wook Chi
- grid.222754.40000 0001 0840 2678Department of Life Sciences, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678Institute of Life Sciences and Biotechnology, Korea University, Seoul, 02481 Republic of Korea ,grid.222754.40000 0001 0840 2678KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02481 Republic of Korea
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14
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Kumari S, Sharma S, Advani D, Khosla A, Kumar P, Ambasta RK. Unboxing the molecular modalities of mutagens in cancer. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:62111-62159. [PMID: 34611806 PMCID: PMC8492102 DOI: 10.1007/s11356-021-16726-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 09/22/2021] [Indexed: 04/16/2023]
Abstract
The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.
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Affiliation(s)
- Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Sudhanshu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Akanksha Khosla
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
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15
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MUTYH-associated tumor syndrome: The other face of MAP. Oncogene 2022; 41:2531-2539. [DOI: 10.1038/s41388-022-02304-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/23/2022] [Accepted: 03/29/2022] [Indexed: 12/13/2022]
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16
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Barreiro RAS, Sabbaga J, Rossi BM, Achatz MIW, Bettoni F, Camargo AA, Asprino PF, A F Galante P. Monoallelic deleterious MUTYH germline variants as a driver for tumorigenesis. J Pathol 2021; 256:214-222. [PMID: 34816434 DOI: 10.1002/path.5829] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/14/2021] [Accepted: 10/28/2021] [Indexed: 01/06/2023]
Abstract
MUTYH encodes a glycosylase involved in the base excision repair of DNA. Biallelic pathogenic germline variants in MUTYH cause an autosomal recessive condition known as MUTYH-associated adenomatous polyposis and consequently increase the risk of colorectal cancer. However, reports of increased cancer risk in individuals carrying only one defective MUTYH allele are controversial and based on studies involving few individuals. Here, we describe a comprehensive investigation of monoallelic pathogenic MUTYH germline variants in 10,389 cancer patients across 33 different tumour types and 117,000 healthy individuals. Our results indicate that monoallelic pathogenic MUTYH germline variants can lead to tumorigenesis through a mechanism of somatic loss of heterozygosity of the functional MUTYH allele in the tumour. We confirmed that the frequency of monoallelic pathogenic MUTYH germline variants is higher in individuals with cancer than in the general population, although this frequency is not homogeneous among tumour types. We also demonstrated that the MUTYH mutational signature is present only in tumours with loss of the functional allele and found that the characteristic MUTYH base substitution (C>A) increases stop-codon generation. We identified key genes that are affected during tumorigenesis. In conclusion, we propose that carriers of the monoallelic pathogenic MUTYH germline variant are at a higher risk of developing tumours, especially those with frequent loss of heterozygosity events, such as adrenal adenocarcinoma, although the overall risk is still low. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Rodrigo Araujo Sequeira Barreiro
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil.,Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Sao Paulo, Brazil
| | - Jorge Sabbaga
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | - Benedito M Rossi
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | | | - Fabiana Bettoni
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | - Anamaria A Camargo
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | - Paula F Asprino
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
| | - Pedro A F Galante
- Centro de Oncologia Molecular, Hospital Sírio-Libanês, São Paulo, Brazil
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17
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Arroyave A, Nodit L, Clegg D, Russ A. Forty-eight-year-old female MUTYH carrier presenting with five concurrent primary cancers. Cancer Rep (Hoboken) 2021; 5:e1455. [PMID: 34173730 PMCID: PMC8842692 DOI: 10.1002/cnr2.1455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 11/16/2022] Open
Abstract
Background MUTYH‐associated polyposis is a rare disorder resulting from mutations involved in DNA mismatch repair. This results in an increased susceptibility to colonic adenomatosis and other cancers. Studies have examined the resulting frequency of extracolonic manifestations; however, these typically occur alone, concurrently, or temporally separate from an already diagnosed colorectal cancer in individuals with a biallelic mutation. Case Reported here is a case of five distinct primary neoplasms presenting simultaneously in a patient monoallelic for an MYH mutation. These neoplasms included squamous cell carcinoma of the vulva, rectal adenocarcinoma, synchronous anal adenocarcinoma, papillary thyroid carcinoma, and ovarian serous psammocarcinoma. Throughout her course, she underwent multiple surgical procedures, neoadjuvant chemoradiation, with further adjuvant therapy, and treatment ongoing. Due to her unique presentation, she underwent genetic testing that demonstrated she was monoallelic for an MYH mutation. Conclusion The patient had a positive response to her treatment and surgical procedures with ongoing adjuvant therapy. She will continue to undergo further genetic testing, and testing for her children is being considered. This case demonstrates a unique presentation associated with a monoallelic MYH mutation that is not described in the current literature and warrants further investigation.
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Affiliation(s)
- Aaron Arroyave
- Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee, USA
| | - Laurentia Nodit
- Department of Pathology, University of Tennessee Medical Center, Knoxville, Tennessee, USA
| | - Devin Clegg
- Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee, USA
| | - Andrew Russ
- Department of Surgery, Colon and Rectal Surgery, University of Tennessee Medical Center, Knoxville, Tennessee, USA
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18
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19
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Patel R, McGinty P, Cuthill V, Hawkins M, Moorghen M, Clark SK, Latchford A. MUTYH-associated polyposis - colorectal phenotype and management. Colorectal Dis 2020; 22:1271-1278. [PMID: 32307808 DOI: 10.1111/codi.15078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 03/11/2020] [Indexed: 12/13/2022]
Abstract
AIM The aim was to determine the presentation, management and outcomes of MUTYH-associated polyposis (MAP). METHOD A prospectively maintained database was used to identify patients with MAP. Demographic data and data on germline mutation, surgical management, histopathology of tumours and endoscopic surveillance were collected. RESULTS In all, 134 patients with MAP were identified. The majority presented symptomatically (n = 83). Sixty-eight patients developed cancer (seven synchronous, 12 metachronous). The median age at diagnosis of first colorectal cancer was 47 years (range 33-74 years). Cancers occurred in the context of a few adenomas (< 10). The majority of patients (n = 108) had surgery as the first line management. One patient received palliative care. Twenty-five patients had endoscopic surveillance as first line management; no cancers occurred in this group. Patients who had segmental resection and postoperative surveillance still appeared to be at risk of metachronous cancer (5/30, 17%). CONCLUSIONS MUTYH testing should be considered even in the context of cancers occurring with fewer than 10 adenomas. In cases of primary colorectal cancers, extended surgery should be considered if patients do not have access to high quality endoscopic surveillance postoperatively. For some patients, endoscopic therapy is an appropriate and safe option in expert hands.
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Affiliation(s)
- R Patel
- Polyposis Registry, St Mark's Hospital, Harrow, UK.,Department of Surgery and Cancer, Imperial College London, London, UK
| | - P McGinty
- Polyposis Registry, St Mark's Hospital, Harrow, UK
| | - V Cuthill
- Polyposis Registry, St Mark's Hospital, Harrow, UK
| | - M Hawkins
- Polyposis Registry, St Mark's Hospital, Harrow, UK
| | - M Moorghen
- Polyposis Registry, St Mark's Hospital, Harrow, UK
| | - S K Clark
- Polyposis Registry, St Mark's Hospital, Harrow, UK.,Department of Surgery and Cancer, Imperial College London, London, UK
| | - A Latchford
- Polyposis Registry, St Mark's Hospital, Harrow, UK.,Department of Surgery and Cancer, Imperial College London, London, UK
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20
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Wang M, Zhu F, Luo N, Han T, Wang M. A case report of a patient with first phenotype of papillary thyroid carcinoma and heterochronous multiprimary tumor harboring germline MUTYH Arg19*/Gly286Glu mutations. Oral Oncol 2020; 112:104987. [PMID: 32888815 DOI: 10.1016/j.oraloncology.2020.104987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 01/01/2023]
Abstract
MUTYH-associated polyposis (MAP) is an autosomal recessively inherited disease with multiple system tumors mainly in alimentary system. Tumor occurrence of MAP patients is highly heterogeneous in space and time. MAP is associated with germline biallelic mutations in MUTYH. The targeted next‑generation sequencing technology and Sanger sequencing are the important methods to screen MUTYH mutations now. Herein, we identified a patient with heterochronous multiprimary tumor carring MUYTH Arg19*/Gly286Glu compound heterozygous mutations. The patient in this case had a first phenotype of thyroid cancer at age 44, which earlier 2 years than the alimentary system cancers. In conclusion, our case report creases the in-depth understanding of the MAP heterogeneous phenotype and further reminds recommendations for improvement of health management and genetic counseling, special treatment plans.
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Affiliation(s)
- Mingbo Wang
- Department of Oncology, Donge People's Hospital, Donge, China
| | - Fuxin Zhu
- Department of Oncology, Donge People's Hospital, Donge, China
| | - Ningning Luo
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Tiantian Han
- The State Key Lab of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Musen Wang
- Department of Pathology, Donge People's Hospital, Donge, China.
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21
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Curia MC, Catalano T, Aceto GM. MUTYH: Not just polyposis. World J Clin Oncol 2020; 11:428-449. [PMID: 32821650 PMCID: PMC7407923 DOI: 10.5306/wjco.v11.i7.428] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/08/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.
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Affiliation(s)
- Maria Cristina Curia
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Via Consolare Valeria 98125, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy
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22
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Abduljaleel Z, Athar M, Al-Allaf FA, Al-Dehlawi S, Vazquez JR. Association of functional variants and protein-to-protein physical interactions of human MutY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome. Noncoding RNA Res 2020; 4:155-173. [PMID: 32072083 PMCID: PMC7012779 DOI: 10.1016/j.ncrna.2019.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Revised: 09/26/2019] [Accepted: 11/19/2019] [Indexed: 11/26/2022] Open
Abstract
The human gene MUTYH codes for a DNA glycosylase involved in the repair of oxidative DNA damage. Faulty MUTYH protein activity causes the accumulation of G→T transversions due to unrepaired 8-oxoG:A mismatches. MUTYH germ-line mutations in humans are linked with a recessive form of Familial Adenomatous Polyposis (FAP) and colorectal cancer predisposition. We studied the repair capacity of variants identified in MUTYH-associated polyposis (MAP) patients. MAP is inherited in an autosomal recessive type due to mutations in MUTYH (Y165C, G382D, P54S, A22V, Q63R, G45D, S136P and N43S), indicating that both copies of the gene become inactivated. However, the parents of an individual with an autosomal recessive condition may serve as carriers, each harboring one copy of the mutated gene without showing signs or symptoms of MAP. Six protein partners have been associated with MUTYH, four via direct physical interactions, namely, hMSH6, hPCNA, hRPA1, and hAPEX1. We examined, for the first time, specific interactions of these protein partners with MAP-associated MUTYH mutants using molecular dynamics simulations. The approach provided tools for exploration of the conformational energy landscape accessible to protein partners. The investigation also determined the impact before and after energy minimization of protein-protein interactions and binding affinities of MUTYH wild type and mutant forms, as well as the interactions with other proteins. Taken together, this study provided new insights into the role of MUTYH and its interacting proteins in MAP.
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Affiliation(s)
- Zainularifeen Abduljaleel
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O.Box: 715, Makkah 21955, Saudi Arabia.,Science and Technology Unit, Umm Al-Qura University, P.O. Box: 715, Makkah 21955, Saudi Arabia.,Bircham University, Av. Sierra, 2, 28691 Villanueva de la Canada, Madrid, Spain
| | - Mohammad Athar
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O.Box: 715, Makkah 21955, Saudi Arabia.,Science and Technology Unit, Umm Al-Qura University, P.O. Box: 715, Makkah 21955, Saudi Arabia
| | - Faisal A Al-Allaf
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, P.O.Box: 715, Makkah 21955, Saudi Arabia.,Science and Technology Unit, Umm Al-Qura University, P.O. Box: 715, Makkah 21955, Saudi Arabia
| | - Saied Al-Dehlawi
- The Regional Laboratory, Ministry of Health (MOH), P.O. Box: 6251, Makkah, Saudi Arabia
| | - Jose R Vazquez
- Bircham University, Av. Sierra, 2, 28691 Villanueva de la Canada, Madrid, Spain
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23
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Simon H, Vartanian V, Wong MH, Nakabeppu Y, Sharma P, Lloyd RS, Sampath H. OGG1 deficiency alters the intestinal microbiome and increases intestinal inflammation in a mouse model. PLoS One 2020; 15:e0227501. [PMID: 31935236 PMCID: PMC6959583 DOI: 10.1371/journal.pone.0227501] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 12/19/2019] [Indexed: 02/07/2023] Open
Abstract
OGG1-deficient (Ogg1-/-) animals display increased propensity to age-induced and diet-induced metabolic diseases, including insulin resistance and fatty liver. Since the intestinal microbiome is increasingly understood to play a role in modulating host metabolic responses, we examined gut microbial composition in Ogg1-/- mice subjected to different nutritional challenges. Interestingly, Ogg1-/- mice had a markedly altered intestinal microbiome under both control-fed and hypercaloric diet conditions. Several microbial species that were increased in Ogg1-/- animals were associated with increased energy harvest, consistent with their propensity to high-fat diet induced weight gain. In addition, several pro-inflammatory microbes were increased in Ogg1-/- mice. Consistent with this observation, Ogg1-/- mice were significantly more sensitive to intestinal inflammation induced by acute exposure to dextran sulfate sodium. Taken together, these data indicate that in addition to their proclivity to obesity and metabolic disease, Ogg1-/- mice are prone to colonic inflammation. Further, these data point to alterations in the intestinal microbiome as potential mediators of the metabolic and intestinal inflammatory response in Ogg1-/- mice.
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Affiliation(s)
- Holly Simon
- Division of Environmental and Biomolecular Systems, Institute of Environmental Health, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Vladimir Vartanian
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Melissa H. Wong
- Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon, United States of America
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Fukuoka, Kyushu, Japan
| | - Priyanka Sharma
- Department of Nutritional Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- New Jersey Institute for Food, Nutrition, and Health, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
| | - R. Stephen Lloyd
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, United States of America
- Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, United States of America
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, Oregon, United States of America
| | - Harini Sampath
- Department of Nutritional Sciences, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- New Jersey Institute for Food, Nutrition, and Health, Rutgers, the State University of New Jersey, New Brunswick, New Jersey, United States of America
- * E-mail:
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Nguyen LH, Goel A, Chung DC. Pathways of Colorectal Carcinogenesis. Gastroenterology 2020; 158:291-302. [PMID: 31622622 PMCID: PMC6981255 DOI: 10.1053/j.gastro.2019.08.059] [Citation(s) in RCA: 262] [Impact Index Per Article: 52.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/13/2019] [Accepted: 08/15/2019] [Indexed: 12/15/2022]
Abstract
Colorectal cancer is a heterogeneous disease that develops via stepwise accumulation of well-characterized genetic and epigenetic alterations. We review the genetic changes associated with the development of precancerous colorectal adenomas and their progression to tumors, as well as the effects of defective DNA repair, chromosome instability, microsatellite instability, and alterations in the serrated pathway and DNA methylation. We provide insights into the different molecular subgroups of colorectal tumors that develop via each of these different mechanisms and their associations with patient outcomes.
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Affiliation(s)
- Long H Nguyen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, Texas; Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas; Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California.
| | - Daniel C Chung
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Center for Cancer Risk Assessment, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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25
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Kdissa A, Brusgaard K, Ksiaa M, Golli L, Hallara O, Ousager LB, Manoubi W, Seghaier RB, Adala L, Halleb Y, Saad A, Hmila F, Gribaa M. c.1227_1228dupGG (p.Glu410Glyfs), a frequent variant in Tunisian patients with MUTYH associated polyposis. Cancer Genet 2019; 240:45-53. [PMID: 31739127 DOI: 10.1016/j.cancergen.2019.10.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 09/25/2019] [Accepted: 10/28/2019] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited disease caused by germline variants in the APC gene. It is characterized by the development of hundreds to thousands of adenomatous polyps in colon and rectum. Recently, biallelic germline variants in the base excision repair (BER) gene: MUTYH have been identified in patients with attenuated FAP and/or negative APC result. It can be responsible for an autosomal recessive inherited colorectal cancer syndrome (MAP syndrome: MUTYH-associated polyposis). OBJECTIVE The aim of this study was to evaluate germline variants of MUTYH gene in Tunisian patients with attenuated FAP. METHODS thirteen unrelated patients from Tunisia with attenuated FAP were screened for MUTYH germline variants. Direct sequencing was performed to identify point variants in this gene. RESULTS A Biallelic MUTYH germline variant were found in all patients and showed an attenuated polyposis phenotype almost of them without extra-colic manifestations: The known pathogenic frameshift variant c.1227_1228dupGG (p. Glu410Glyfs) was found, in homozygous state, in 13 index patients. CONCLUSION Patients with attenuated familial adenomatous polyposis (<=100) and no obvious vertical transmission of the disease should be considered for MUTYH gene testing.
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Affiliation(s)
- Ameni Kdissa
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia.
| | - Klaus Brusgaard
- Amplexa Genetics A/S, Odense, Denmark; Department of Clinical Genetics, Odense University Hospital, Odense, Denmark; Department of Medical Genetics, Near East University, Nicosia, Northern Cyprus
| | - Mahdi Ksiaa
- Department of gastroenterology, Sahloul University Hospital, Sousse, Tunisia
| | - Lamia Golli
- Private cabinet of gastroenterology, Sousse, Tunisia
| | - Olfa Hallara
- Department of gastroenterology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | | | - Wiem Manoubi
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
| | - Rihab Ben Seghaier
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
| | - Labiba Adala
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
| | - Yosra Halleb
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
| | - Ali Saad
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
| | - Fahmi Hmila
- Department of General Surgery, Farhat Hached, University Hospital, Sousse, Tunisia
| | - Moez Gribaa
- Cytogenetic, Molecular Genetics and Human Reproduction Biology - FARHAT HACHED University Hospital, Sousse, Tunisia
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26
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Babaei K, Khaksar R, Zeinali T, Hemmati H, Bandegi A, Samidoust P, Ashoobi MT, Hashemian H, Delpasand K, Talebinasab F, Naebi H, Mirpour SH, Keymoradzadeh A, Norollahi SE. Epigenetic profiling of MUTYH, KLF6, WNT1 and KLF4 genes in carcinogenesis and tumorigenesis of colorectal cancer. Biomedicine (Taipei) 2019; 9:22. [PMID: 31724937 PMCID: PMC6855188 DOI: 10.1051/bmdcn/2019090422] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 09/02/2019] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is distinguished by epigenetic elements like DNA methylation, histone modification, histone acetylation and RNA remodeling which is related with genomic instability and tumor initiation. Correspondingly, as a main epigenetic regulation, DNA methylation has an impressive ability in order to be used in CRC targeted therapy. Meaningly, DNA methylation is identified as one of most important epigenetic regulators in gene expression and is considered as a notable potential driver in tumorigenesis and carcinogenesis through gene-silencing of tumor suppressors genes. Abnormal methylation situation, even in the level of promoter regions, does not essentially change the gene expression levels, particularly if the gene was become silenced, leaving the mechanisms of methylation without any response. According to the methylation situation which has a strong eagerness to be highly altered on CpG islands in carcinogenesis and tumorigenesis, considering its epigenetic fluctuations in finding new biomarkers is of great importance. Modifications in DNA methylation pattern and also enrichment of methylated histone signs in the promoter regions of some certain genes like MUTYH, KLF4/6 and WNT1 in different signaling pathways could be a notable key contributors to the upregulation of tumor initiation in CRC. These epigenetic alterations could be employed as a practical diagnostic biomarkers for colorectal cancer. In this review, we will be discuss these fluctuations of MUTYH, KLF4/6 and WNT1 genes in CRC.
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Affiliation(s)
- Kosar Babaei
- Department of Biology, Islamic Azad University of Tonekabon Branch, Tonekabon, Iran
| | - Roya Khaksar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Tahereh Zeinali
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Hossein Hemmati
- Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht, Iran
| | - Ahmadreza Bandegi
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Pirouz Samidoust
- Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammad Taghi Ashoobi
- Department of Surgery, Poursina Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Hooman Hashemian
- Pediatric Diseases Research Center,Guilan University of Medical ciences, Rasht, Iran
| | - Kourosh Delpasand
- School of Medicine, Kurdistan University of Mdical Ciences, Sanandaj, Iran
| | - Fereshteh Talebinasab
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Hoora Naebi
- Department of Biochemistry, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed Hossein Mirpour
- Department of Hematology and Oncology, Razi hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Arman Keymoradzadeh
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Seyedeh Elham Norollahi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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DeLeonardis K, Hogan L, Cannistra SA, Rangachari D, Tung N. When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing? J Oncol Pract 2019; 15:465-473. [DOI: 10.1200/jop.19.00201] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Somatic genomic testing is rapidly becoming an integral part of care for patients with metastatic cancer. Extrapolation of these results beyond personalized cancer therapy is a skill being demanded of practicing oncologists without prior specialty in genetics. Up to 12% of tumor genomic profiling reports will reveal a germline pathogenic variant. Recognition of these germline variants is essential not only for optimal care of the patient with cancer but also to initiate cascade genetic testing in at-risk family members who also may carry the familial mutation. This article provides a concise and methodical, evidence-based strategy to guide oncology providers about how to identify genes associated with an inherited predisposition for cancer, determine the pathogenicity of variants reported within those genes, and understand the likelihood that these variants are of germline origin in a particular patient with cancer. Case examples are provided to illustrate clinical scenarios and facilitate application of the proposed approach.
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Affiliation(s)
| | - Lauren Hogan
- Beth Israel Deaconess Medical Center, Boston, MA
| | | | | | - Nadine Tung
- Beth Israel Deaconess Medical Center, Boston, MA
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28
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Li N, Kang Q, Yang L, Zhao XJ, Xue LJ, Wang X, Li AQ, Li CG, Sheng JQ. Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China. J Gastroenterol Hepatol 2019; 34:1497-1503. [PMID: 31062380 DOI: 10.1111/jgh.14704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Revised: 04/25/2019] [Accepted: 04/30/2019] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype-phenotype correlation in mutated patients. METHODS Mutation screening of 46 unrelated probands was performed using multigene panels by next-generation sequencing. Clinical data of the index were used to assess genotype-phenotype correlations. RESULTS Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. CONCLUSION In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.
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Affiliation(s)
- Na Li
- Medical School of Chinese PLA, Beijing, China.,Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Qian Kang
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Lang Yang
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Xiao-Jun Zhao
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Li-Jun Xue
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Xin Wang
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Ai-Qin Li
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Chen-Guang Li
- Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
| | - Jian-Qiu Sheng
- Medical School of Chinese PLA, Beijing, China.,Department of Gastroenterology, The Seventh Medical Center of PLA General Hospital, Beijing, China
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Kay J, Thadhani E, Samson L, Engelward B. Inflammation-induced DNA damage, mutations and cancer. DNA Repair (Amst) 2019; 83:102673. [PMID: 31387777 DOI: 10.1016/j.dnarep.2019.102673] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 06/15/2019] [Accepted: 07/18/2019] [Indexed: 12/22/2022]
Abstract
The relationships between inflammation and cancer are varied and complex. An important connection linking inflammation to cancer development is DNA damage. During inflammation reactive oxygen and nitrogen species (RONS) are created to combat pathogens and to stimulate tissue repair and regeneration, but these chemicals can also damage DNA, which in turn can promote mutations that initiate and promote cancer. DNA repair pathways are essential for preventing DNA damage from causing mutations and cytotoxicity, but RONS can interfere with repair mechanisms, reducing their efficacy. Further, cellular responses to DNA damage, such as damage signaling and cytotoxicity, can promote inflammation, creating a positive feedback loop. Despite coordination of DNA repair and oxidative stress responses, there are nevertheless examples whereby inflammation has been shown to promote mutagenesis, tissue damage, and ultimately carcinogenesis. Here, we discuss the DNA damage-mediated associations between inflammation, mutagenesis and cancer.
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Affiliation(s)
- Jennifer Kay
- Department of Biological Engineering, United States.
| | | | - Leona Samson
- Department of Biological Engineering, United States; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, United States
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30
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The role of inherited genetic variants in colorectal polyposis syndromes. ADVANCES IN GENETICS 2019; 103:183-217. [PMID: 30904095 DOI: 10.1016/bs.adgen.2018.11.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal carcinoma (CRC) is the third most common cancer in men and the second most common cancer in women across the world. Most CRCs occur sporadically, but in 15-35% of cases, hereditary factors are important. Some patients with an inherited predisposition to CRC will be diagnosed with a "genetic polyposis syndrome" such as familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), polymerase proofreading associated polyposis (PPAP), NTHL1-associated polyposis, MSH3-associated polyposis or a hamartomatous polyposis syndrome. Individuals with ≥10 colorectal polyps have traditionally been referred for genetic diagnostic testing to identify APC and MUTYH mutations which cause FAP and MAP respectively. Mutations are found in most patients with >100 adenomas but in only a minority of those with 10-100 adenomas. The reasons that diagnostic laboratories are not identifying pathogenic variants include mutations occurring outside of the open reading frames of genes, individuals exhibiting generalized mosaicism and the involvement of additional genes. It is important to identify patients with an inherited polyposis syndrome, and to define the mutations causing their polyposis, so that the individuals and their relatives can be managed appropriately.
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31
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Sakurada A, Miyanishi K, Tanaka S, Sato M, Sakamoto H, Kawano Y, Takada K, Nakabeppu Y, Kobune M, Kato J. An intronic single nucleotide polymorphism in the MUTYH gene is associated with increased risk for HCV-induced hepatocellular carcinoma. Free Radic Biol Med 2018; 129:88-96. [PMID: 30218772 DOI: 10.1016/j.freeradbiomed.2018.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 08/30/2018] [Accepted: 09/11/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS The role of base excision repair genes in human hepatocarcinogenesis has not yet been explored. Here, we investigated relationships between variants of these genes and the risk of developing hepatocellular carcinoma (HCC). METHODS Nineteen tagging SNPs in base excision repair genes (including MUTYH, OGG1 and MTH1) were genotyped using iPLEX assays; one significant SNP was found and confirmed in Japanese patients with chronic hepatitis C (CHC) (n = 38 HCC and 55 controls). The effects of modifying the intronic variants were determined by luciferase assays. MUTYH-null mice were used to examine the involvement of oxidative stress and DNA repair enzymes in hepatocarcinogenesis. RESULTS Significant associations were found for a single intron SNP (rs3219487) in the MUTYH gene. The risk of developing HCC in patients with A/A or G/A genotypes was higher than in those with the G/G genotype (OR = 9.27, 95% CI = 2.39 -32.1, P = 0.0005). MUTYH mRNA levels in both peripheral mononuclear cells were significantly lower in G/A or A/A genotyped subjects (P = 0.0157 and 0.0108, respectively). We found that -2000 in the MUTYH promoter region is involved in enhanced expression of MUTYH by insertion of a major allele sequence of rs3219487. Liver tumors were observed in MUTYH-null mice after 12 months´ high iron diet, but no tumors developed when dietary anti-oxidant (N-Acetyl-L-cysteine) was also provided. CONCLUSIONS CHC patients with the rs3219487 adenine allele had a significantly increased risk of developing HCC. MUTYH-null mice with iron-associated oxidative stress were susceptible to development of liver tumors unless prevented by dietary anti-oxidants.
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MESH Headings
- Aged
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Case-Control Studies
- DNA Glycosylases/genetics
- DNA Repair Enzymes/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Genotype
- Hep G2 Cells
- Hepacivirus/pathogenicity
- Hepacivirus/physiology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Introns
- Iron/administration & dosage
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphoric Monoester Hydrolases/genetics
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Reactive Oxygen Species/metabolism
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Affiliation(s)
- Akira Sakurada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
| | - Shingo Tanaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroki Sakamoto
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yutaka Kawano
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yusaku Nakabeppu
- Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
| | - Masayoshi Kobune
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan.
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Rosenthal EA, Shirts BH, Amendola LM, Horike-Pyne M, Robertson PD, Hisama FM, Bennett RL, Dorschner MO, Nickerson DA, Stanaway IB, Nassir R, Vickers KT, Li C, Grady WM, Peters U, Jarvik GP. Rare loss of function variants in candidate genes and risk of colorectal cancer. Hum Genet 2018; 137:795-806. [PMID: 30267214 PMCID: PMC6283057 DOI: 10.1007/s00439-018-1938-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/18/2018] [Indexed: 02/07/2023]
Abstract
Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.
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Affiliation(s)
- Elisabeth A Rosenthal
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA.
| | - Brian H Shirts
- Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, WA, USA
| | - Laura M Amendola
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Martha Horike-Pyne
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Peggy D Robertson
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Fuki M Hisama
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA
- Department of Neurology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Robin L Bennett
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA
| | - Michael O Dorschner
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
- Department of Psychiatry and Behavioral Sciences, School of Medicine, University of Washington, Seattle, WA, USA
| | | | - Ian B Stanaway
- Department of Biomedical Informatics and Medical Education, School of Medicine, University of Washington, Seattle, WA, USA
| | - Rami Nassir
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
| | - Kathy T Vickers
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Christopher Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Gail P Jarvik
- Division of Medical Genetics, School of Medicine, University of Washington Medical Center, Seattle, WA, USA
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
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33
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Nascimento EFR, Ribeiro ML, Magro DO, Carvalho J, Kanno DT, Martinez CAR, Coy CSR. TISSUE EXPRESION OF THE GENES MUTYH AND OGG1 IN PATIENTS WITH SPORADIC COLORECTAL CANCER. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2018; 30:98-102. [PMID: 29257843 PMCID: PMC5543786 DOI: 10.1590/0102-6720201700020005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 03/14/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND MTUYH and OGG1 genes have importance in the base excision repair systems of oxidized DNA bases. Modification of the tissue expression of these genes is related to the increased risk of developing colorectal cancer. AIM To evaluate the tissue expression of MUTYH and OGG1 comparing normal and neoplastic tissues of patients with sporadic colorectal cancer and to correlate it with clinical and histopathological variables. METHOD MUTYH and OGG1 tissue expression was quantified by RT-PCR in patients with colorectal cancer and the values were compared in normal and neoplastic tissues. MUTYH and OGG1 expression was measured and normalized to the constitutive 18S gene. The level of expression of both genes was correlated with the variables: age, gender, tumor location, size of the tumor, histological type, degree of cell differentiation, invasion depth in the intestinal wall, angiolymphatic infiltration, lymph node involvement and TNM staging. RESULTS Was found downregulation of both genes in neoplastic when compared to normal tissue. There was downregulation of the MUTYH in larger tumors and in patients with angiolymphatic invasion. Tumors with more advanced TNM stages (III and IV) presented downregulation of both genes when compared to those with earlier stages (I and II). CONCLUSION The MUTYH and OGG1 genes present downregulation in the more advanced stages of colorectal cancer.
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Affiliation(s)
- Enzo Fabrício Ribeiro Nascimento
- Faculty of Medical Sciences of the State University of Campinas (FCM-UNICAMP), Postgraduate Program in Surgery Sciences, Campinas, SP
| | - Marcelo Lima Ribeiro
- São Francisco University, Post-Graduation Program in Health Sciences, Bragança Paulista, SP
| | - Daniela Oliveira Magro
- Faculty of Medical Sciences of the State University of Campinas, Department of Surgery, Campinas, SP
| | - Juliana Carvalho
- State University of Campinas, Integrated Center for Women's Health Care, Campinas, SP, Brazil
| | - Danilo Toshio Kanno
- São Francisco University, Post-Graduation Program in Health Sciences, Bragança Paulista, SP
| | - Carlos Augusto Real Martinez
- São Francisco University, Post-Graduation Program in Health Sciences, Bragança Paulista, SP.,Faculty of Medical Sciences of the State University of Campinas, Department of Surgery, Campinas, SP
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Anandappa G, Chau I. Evolving Tissue and Circulating Biomarkers as Prognostic and Predictive Tools in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2018. [DOI: 10.1007/s11888-018-0410-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood. Clin Cancer Res 2018; 23:e107-e114. [PMID: 28674119 DOI: 10.1158/1078-0432.ccr-17-0790] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/08/2017] [Accepted: 05/12/2017] [Indexed: 11/16/2022]
Abstract
Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz-Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107-e14. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
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Affiliation(s)
- Maria Isabel Achatz
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
| | | | - Laurence Brugières
- Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France
| | - Harriet Druker
- Division of Hematology/Oncology, Department of Genetic Counselling, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Thierry Frebourg
- Department of Genetics, Rouen University Hospital, Rouen, France
| | - William D Foulkes
- Department of Medicine, Oncology and Human Genetics, McGill University, Montreal, Canada
| | - Christian P Kratz
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Roland P Kuiper
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Jordan R Hansford
- Children's Cancer Centre, Royal Children's Hospital; Murdoch Children's Research Institute; University of Melbourne, Melbourne, Australia
| | | | | | - Wendy K Kohlmann
- Population Health Sciences Department, Huntsman Cancer Institute, Salt Lake City, Utah
| | - Leslie Doros
- Cancer Genetics Clinic, Children's National Medical Center, Washington, DC
| | - Kenan Onel
- Department of Pediatrics, Hofstra-Northwell School of Medicine and Cohen Children's Medical Center, Manhasset, New York
| | - Kami Wolfe Schneider
- Division of Hematology, Oncology, Bone Marrow Transplant, Children's Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Sarah R Scollon
- Department of Pediatrics, Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas
| | - Uri Tabori
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Gail E Tomlinson
- Department of Pediatric Hematology-Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
| | - D Gareth R Evans
- Department of Genomic Medicine, University of Manchester, St. Mary's Hospital, Manchester, United Kingdom
| | - Sharon E Plon
- Department of Pediatrics, Division of Hematology/Oncology, Baylor College of Medicine, Houston, Texas
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Common Genetic Variants of MUTYH are not Associated with Cutaneous Malignant Melanoma: Application of Molecular Screening by Means of High-Resolution Melting Technique in a Pilot Case-Control Study. Int J Biol Markers 2018; 26:37-42. [DOI: 10.5301/jbm.2011.6285] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2010] [Indexed: 01/09/2023]
Abstract
MUTYH glycosylase recognizes the 8-oxoG:A mismatch and is able to excise the adenine base using proofreading mechanisms. Some papers have reported a strong association between cancer development or aggressiveness and MUTYH gene mutations. The aim of this study was to find a possible association between the most frequent MUTYH mutations and melanoma in the context of a case-control pilot study. One hundred ninety-five melanoma patients and 195 healthy controls were matched for sex and age. Clinical and laboratory data were collected in a specific database and all individuals were analyzed for MUTYH mutations by high-resolution melting and direct sequencing techniques. Men and women had significantly different distributions of tumor sites and phototypes. No significant associations were observed between the Y165C, G382D and V479F MUTYH mutations and risk of melanoma development or aggressiveness. Our preliminary findings therefore do not confirm a role for MUTYH gene mutations in the melanoma risk. Further studies are necessary for the assessment of MUTYH not only in melanoma but also other cancer types with the same embryonic origin, in the context of larger arrays studies of genes involved in DNA stability or integrity.
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Tan SC. Low penetrance genetic polymorphisms as potential biomarkers for colorectal cancer predisposition. J Gene Med 2018; 20:e3010. [PMID: 29424105 DOI: 10.1002/jgm.3010] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/12/2018] [Accepted: 01/19/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is a leading form of cancer in both males and females. Early detection of individuals at risk of colorectal cancer allows proper treatment and management of the disease to be implemented, which can potentially reduce the burden of colorectal cancer incidence, morbidity and mortality. In recent years, the role of genetic susceptibility factors in mediating predisposition to colorectal cancer has become more and more apparent. Identification of high-frequency, low-penetrance genetic polymorphisms associated with the cancer has therefore emerged as an important approach which can potentially aid prediction of colorectal cancer risk. However, the overwhelming amount of genetic epidemiology data generated over the past decades has made it difficult for one to assimilate the information and determine the exact genetic polymorphisms that can potentially be used as biomarkers for colorectal cancer. This review comprehensively consolidates, based primarily on results from meta-analyses, the recent progresses in the search of colorectal cancer-associated genetic polymorphisms, and discusses the possible mechanisms involved.
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Affiliation(s)
- Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Zorcolo L, Fantola G, Balestrino L, Restivo A, Vivanet C, Spina F, Cabras F, Ambu R, Casula G. MUTYH-associated colon disease: Adenomatous polyposis is only one of the possible phenotypes. A family report and literature review. TUMORI JOURNAL 2018; 97:676-80. [DOI: 10.1177/030089161109700523] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Aims and background The MutY human homologue gene (MUTYH) is responsible for about a quarter of attenuated familial adenomatous polyposis. Occasionally, it has been associated with hyperplastic polyps and serrated adenoma. We report a family where the same MUTYH mutation determined four different phenotypes, including a case of hyperplastic polyposis syndrome. Patients and methods A family with a history of right-sided colon cancer and multiple colonic polyposis was investigated. Genetic tests were correlated with clinical findings to define phenotypic manifestations of MUTYH mutations. The pertinent English-language literature was reviewed to evaluate the risk of malignancy of MUTYH and the role of prophylactic surgery. Results Three male siblings carried a biallelic MUTYH mutation (G382D-exon13), while the fourth was heterozygote. One developed an isolated cecal cancer at the age of 48. Another, aged 38, was diagnosed with numerous minute colonic and rectal polyps and underwent a proctocolectomy, with final pathology showing a picture of hyperplastic and lymphoid polyposis. The third biallelic brother, 46 years old, developed four hyperplastic lesions, while the heterozygote brother had a large flat serrated adenoma of the right colon removed at the age of 50. Conclusion Many aspects of MUTYH mutation still need to be clarified and one of them regards the different phenotypic expressions. Although the majority of reported cases manifested attenuated adenomatous polyposis, hyperplastic polyps and serrated adenomas appear to be more common than expected. Presenting hyperplastic polyposis syndrome is very unusual and may represent a clinical dilemma for correct management. Current evidence suggests to handle MUTYH-associated polyposis as typical FAP.
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Affiliation(s)
- Luigi Zorcolo
- Department of General Surgery, Colorectal Unit, University of Cagliari, Cagliari
| | - Giovanni Fantola
- Department of General Surgery, Colorectal Unit, University of Cagliari, Cagliari
| | | | - Angelo Restivo
- Department of General Surgery, Colorectal Unit, University of Cagliari, Cagliari
| | | | | | - Francesco Cabras
- Department of General Surgery, Colorectal Unit, University of Cagliari, Cagliari
| | - Rossano Ambu
- Department of Pathology, University of Cagliari, Cagliari, Italy
| | - Giuseppe Casula
- Department of General Surgery, Colorectal Unit, University of Cagliari, Cagliari
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Pathology and genetics of hereditary colorectal cancer. Pathology 2018; 50:49-59. [DOI: 10.1016/j.pathol.2017.09.004] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 09/11/2017] [Indexed: 12/15/2022]
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In vivo measurements of interindividual differences in DNA glycosylases and APE1 activities. Proc Natl Acad Sci U S A 2017; 114:E10379-E10388. [PMID: 29122935 DOI: 10.1073/pnas.1712032114] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The integrity of our DNA is challenged with at least 100,000 lesions per cell on a daily basis. Failure to repair DNA damage efficiently can lead to cancer, immunodeficiency, and neurodegenerative disease. Base excision repair (BER) recognizes and repairs minimally helix-distorting DNA base lesions induced by both endogenous and exogenous DNA damaging agents. Levels of BER-initiating DNA glycosylases can vary between individuals, suggesting that quantitating and understanding interindividual differences in DNA repair capacity (DRC) may enable us to predict and prevent disease in a personalized manner. However, population studies of BER capacity have been limited because most methods used to measure BER activity are cumbersome, time consuming and, for the most part, only allow for the analysis of one DNA glycosylase at a time. We have developed a fluorescence-based multiplex flow-cytometric host cell reactivation assay wherein the activity of several enzymes [four BER-initiating DNA glycosylases and the downstream processing apurinic/apyrimidinic endonuclease 1 (APE1)] can be tested simultaneously, at single-cell resolution, in vivo. Taking advantage of the transcriptional properties of several DNA lesions, we have engineered specific fluorescent reporter plasmids for quantitative measurements of 8-oxoguanine DNA glycosylase, alkyl-adenine DNA glycosylase, MutY DNA glycosylase, uracil DNA glycosylase, and APE1 activity. We have used these reporters to measure differences in BER capacity across a panel of cell lines collected from healthy individuals, and to generate mathematical models that predict cellular sensitivity to methylmethane sulfonate, H2O2, and 5-FU from DRC. Moreover, we demonstrate the suitability of these reporters to measure differences in DRC in multiple pathways using primary lymphocytes from two individuals.
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Abstract
Colorectal cancer (CRC) is a heterogeneous triat that involves both environmental and genetic factors. Genetic mutations of MUTYH (p.Y179C and p.G396D) have been reported to be associated with increased risk of CRC among several ethnic populations. The aim of this work is to assess the association of the monoallelic MUTYH mutations (p.Y179C and p.G396D) with increased risk of CRC among Egyptian patients. This study included 120 unrelated CRC Egyptian patients who were compared with 100 healthy controls from the same locality. For all individuals, DNA was genotyped for MUTYH p.Y179C and MUTYH p.G396D mutations using the T-ARMS-PCR technique. The frequencies of monoallelic MUTYH mutations showed a strong association with the increased risk of CRC among Egyptian patients compared with controls (12.5 vs. 4.0 %, OR = 3.49, 95 % CI = 1.12-10.90, P = 0.03). Moreover, the frequency of MUTYH p.Y179C mutation was noted to be significantly higher among CRC patients compared to controls rather than MUTYH p.G396D mutation. Interestingly, CRC patients with tumors in the right side colon showed an evidence for association with the MUTYH p.Y179C mutation compared with tumors in the left side colon (p = 0.01). MUTYH p.Y179C mutation was associated with an increased risk of CRC among Egyptian patients rather than MUTYH p.G396D mutation.
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O'Leary E, Iacoboni D, Holle J, Michalski ST, Esplin ED, Yang S, Ouyang K. Expanded Gene Panel Use for Women With Breast Cancer: Identification and Intervention Beyond Breast Cancer Risk. Ann Surg Oncol 2017; 24:3060-3066. [PMID: 28766213 PMCID: PMC5594040 DOI: 10.1245/s10434-017-5963-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Indexed: 12/12/2022]
Abstract
Background Clinicians ordering multi-gene next-generation sequencing panels for hereditary breast cancer risk have a variety of test panel options. Many panels include lesser known breast cancer genes or genes associated with other cancers. The authors hypothesized that using broader gene panels increases the identification of clinically significant findings, some relevant and others incidental to the testing indication. They examined clinician ordering patterns and compared the yield of pathogenic or likely pathogenic (P/LP) variants in non-BRCA genes of female breast cancer patients. Methods This study analyzed de-identified personal and family histories in 1085 breast cancer cases with P/LP multi-gene panel findings in non-BRCA cancer genes and sorted them into three groups by the panel used for testing: group A (breast cancer genes only), group B (commonly assessed cancers: breast, gynecologic, and gastrointestinal), and group C (a more expanded set of tumors). The frequency of P/LP variants in genes with established management guidelines was compared and evaluated for consistency with personal and family histories. Results This study identified 1131 P/LP variants and compared variants in clinically actionable genes for breast and non-breast cancers. Overall, 91.5% of these variants were in genes with management guidelines. Nearly 12% were unrelated to personal or family history. Conclusion Broader panels were used for 85.6% of our cohort (groups B and C). Although pathogenic variants in non-BRCA genes are reportedly rare, the study found that most were in clinically actionable genes. Expanded panel testing improved the identification of hereditary cancer risk. Small, breast-limited panels may miss clinically relevant findings in genes associated with other heritable cancers. Electronic supplementary material The online version of this article (doi:10.1245/s10434-017-5963-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Erin O'Leary
- , 1400 16th Street, San Francisco, CA, 94103, USA.
| | | | | | | | | | - Shan Yang
- , 1400 16th Street, San Francisco, CA, 94103, USA
| | - Karen Ouyang
- , 1400 16th Street, San Francisco, CA, 94103, USA
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Banda DM, Nuñez NN, Burnside MA, Bradshaw KM, David SS. Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine. Free Radic Biol Med 2017; 107:202-215. [PMID: 28087410 PMCID: PMC5457711 DOI: 10.1016/j.freeradbiomed.2017.01.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 01/01/2017] [Accepted: 01/04/2017] [Indexed: 12/12/2022]
Abstract
Reactive oxygen and nitrogen species (RONS) may infringe on the passing of pristine genetic information by inducing DNA inter- and intra-strand crosslinks, protein-DNA crosslinks, and chemical alterations to the sugar or base moieties of DNA. 8-Oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent DNA lesions formed by RONS and is repaired through the base excision repair (BER) pathway involving the DNA repair glycosylases OGG1 and MUTYH in eukaryotes. MUTYH removes adenine (A) from 8-oxoG:A mispairs, thus mitigating the potential of G:C to T:A transversion mutations from occurring in the genome. The paramount role of MUTYH in guarding the genome is well established in the etiology of a colorectal cancer predisposition syndrome involving variants of MUTYH, referred to as MUTYH-associated polyposis (MAP). In this review, we highlight recent advances in understanding how MUTYH structure and related function participate in the manifestation of human disease such as MAP. Here we focus on the importance of MUTYH's metal cofactor sites, including a recently discovered "Zinc linchpin" motif, as well as updates to the catalytic mechanism. Finally, we touch on the insight gleaned from studies with MAP-associated MUTYH variants and recent advances in understanding the multifaceted roles of MUTYH in the cell, both in the prevention of mutagenesis and tumorigenesis.
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Affiliation(s)
- Douglas M Banda
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States
| | - Nicole N Nuñez
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States
| | - Michael A Burnside
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States
| | - Katie M Bradshaw
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States
| | - Sheila S David
- Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, United States.
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Novel mutations and phenotypic associations identified through APC, MUTYH, NTHL1, POLD1, POLE gene analysis in Indian Familial Adenomatous Polyposis cohort. Sci Rep 2017; 7:2214. [PMID: 28533537 PMCID: PMC5440391 DOI: 10.1038/s41598-017-02319-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 04/10/2017] [Indexed: 02/07/2023] Open
Abstract
Colo-Rectal Cancer is a common cancer worldwide with 5-10% cases being hereditary. Familial Adenomatous Polyposis (FAP) syndrome is due to germline mutations in the APC or rarely MUTYH gene. NTHL1, POLD1, POLE have been recently reported in previously unexplained FAP cases. Unlike the Caucasian population, FAP phenotype and its genotypic associations have not been widely studied in several geoethnic groups. We report the first FAP cohort from South Asia and the only non-Caucasian cohort with comprehensive analysis of APC, MUTYH, NTHL1, POLD1, POLE genes. In this cohort of 112 individuals from 53 FAP families, we detected germline APC mutations in 60 individuals (45 families) and biallelic MUTYH mutations in 4 individuals (2 families). No NTHL1, POLD1, POLE mutations were identified. Fifteen novel APC mutations and a new Indian APC mutational hotspot at codon 935 were identified. Eight very rare FAP phenotype or phenotypes rarely associated with mutations outside specific APC regions were observed. APC genotype-phenotype association studies in different geo-ethnic groups can enrich the existing knowledge about phenotypic consequences of distinct APC mutations and guide counseling and risk management in different populations. A stepwise cost-effective mutation screening approach is proposed for genetic testing of south Asian FAP patients.
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Rey JM, Ducros V, Pujol P, Wang Q, Buisine MP, Aissaoui H, Maudelonde T, Olschwang S. Improving Mutation Screening in Patients with Colorectal Cancer Predisposition Using Next-Generation Sequencing. J Mol Diagn 2017; 19:589-601. [PMID: 28502729 DOI: 10.1016/j.jmoldx.2017.04.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/03/2017] [Accepted: 04/10/2017] [Indexed: 12/25/2022] Open
Abstract
Identification of genetic alterations is important for family risk assessment in colorectal cancers. Next-generation sequencing (NGS) technologies provide useful tools for single-nucleotide and copy number variation (CNV) identification in many genes and samples simultaneously. Herein, we present the validation of current Multiplicom MASTR designs of mismatch repair combined to familial adenomatous polyposis genes in a single PCR reamplification test for eight DNA samples simultaneously on a MiSeq apparatus. Blood samples obtained from 224 patients were analyzed. We correctly identified the 97 mutations selected among 48 samples tested in a validation cohort. PMS2 NGS analysis of the eight positive controls identified single-nucleotide variations not detected with targeted referent methods. As NGS method could not discriminate if some of them were assigned to PMS2 or pseudogenes, only CNV analysis with multiplex ligand probe-dependent amplification confirmation was retained for clinical use. Twenty-seven new variants of unknown significance, 21 disease-causing variants, and two CNVs were detected among the 176 patient samples analyzed in diagnosis routine. MUTYH disease-causing mutations were identified in two patient samples assessed for mismatch repair testing, confirming that this method facilitates accurate and rapid individual risk assessments. In one sample, the MUTYH mutation was associated with a MSH6 disease-causing mutation, suggesting that this method is helpful to identify additional cancer risk modifiers and provides a useful tool to optimize clinical issues.
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Affiliation(s)
- Jean-Marc Rey
- Laboratoire de Biopathologie Cellulaire et Tissulaire des Tumeurs, Arnaud de Villeneuve Hospital, Montpellier, France.
| | - Vincent Ducros
- Laboratoire de Biopathologie Cellulaire et Tissulaire des Tumeurs, Arnaud de Villeneuve Hospital, Montpellier, France
| | - Pascal Pujol
- Oncogenetic Department, Arnaud de Villeneuve Hospital, Montpellier, France
| | - Qing Wang
- Laboratoire de Génétique Constitutionnelle des Cancers Fréquents, Léon Bérard Center, Lyon, France
| | - Marie-Pierre Buisine
- Laboratoire de Biochimie et Biologie Moléculaire, Oncologie et Génétique Moléculaire, Center de Biologie Pathologie, CHRU Lille, Lille, France
| | | | - Thierry Maudelonde
- Laboratoire de Biopathologie Cellulaire et Tissulaire des Tumeurs, Arnaud de Villeneuve Hospital, Montpellier, France; Montpellier University, EA2415, Institut Universitaire de Recherche Clinique, Montpellier, France
| | - Sylviane Olschwang
- INSERM UMR_S910, Aix-Marseille University, Ramsay Générale de Santé Clairval Hospital, Marseille, France
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Stephens MC, Boardman LA, Lazaridis KN. Individualized Medicine in Gastroenterology and Hepatology. Mayo Clin Proc 2017; 92:810-825. [PMID: 28473040 DOI: 10.1016/j.mayocp.2017.03.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 02/23/2017] [Accepted: 03/02/2017] [Indexed: 02/08/2023]
Abstract
After the completion of the Human Genome Project, there has been an acceleration in methodologies on sequencing nucleic acids (DNA and RNA) at a high precision and with ever-decreasing turnaround time and cost. Collectively, these approaches are termed next-generation sequencing and are already affecting the transformation of medical practice. In this symposium article, we highlight the current knowledge of the genetics of selected gastrointestinal tract and liver diseases, namely, inflammatory bowel disease, hereditary cholestatic liver disease, and familial colon cancer syndromes. In addition, we provide a stepwise approach to use next-generation sequencing methodologies for clinical practice with the goal to improve the diagnosis as well as management of and/or therapy of the chosen digestive diseases. This early experience of applying next-generation sequencing in the practice of gastroenterology and hepatology will delineate future best practices in the field, ultimately for the benefit of our patients.
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Affiliation(s)
- Michael C Stephens
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN
| | - Lisa A Boardman
- Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN
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A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer. EBioMedicine 2017; 20:39-49. [PMID: 28551381 PMCID: PMC5478212 DOI: 10.1016/j.ebiom.2017.04.022] [Citation(s) in RCA: 144] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/07/2017] [Accepted: 04/11/2017] [Indexed: 01/17/2023] Open
Abstract
8-Oxoguanine, a common mutagenic DNA lesion, generates G:C>T:A transversions via mispairing with adenine during DNA replication. When operating normally, the MUTYH DNA glycosylase prevents 8-oxoguanine-related mutagenesis by excising the incorporated adenine. Biallelic MUTYH mutations impair this enzymatic function and are associated with colorectal cancer (CRC) in MUTYH-Associated Polyposis (MAP) syndrome. Here, we perform whole-exome sequencing that reveals a modest mutator phenotype in MAP CRCs compared to sporadic CRC stem cell lines or bulk tumours. The excess G:C>T:A transversion mutations in MAP CRCs exhibits a novel mutational signature, termed Signature 36, with a strong sequence dependence. The MUTYH mutational signature reflecting persistent 8-oxoG:A mismatches occurs frequently in the APC, KRAS, PIK3CA, FAT4, TP53, FAT1, AMER1, KDM6A, SMAD4 and SMAD2 genes that are associated with CRC. The occurrence of Signature 36 in other types of human cancer indicates that DNA 8-oxoguanine-related mutations might contribute to the development of cancer in other organs.
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Furlan D, Trapani D, Berrino E, Debernardi C, Panero M, Libera L, Sahnane N, Riva C, Tibiletti MG, Sessa F, Sapino A, Venesio T. Oxidative DNA damage induces hypomethylation in a compromised base excision repair colorectal tumourigenesis. Br J Cancer 2017; 116:793-801. [PMID: 28141798 PMCID: PMC5355935 DOI: 10.1038/bjc.2017.9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 12/23/2016] [Accepted: 01/05/2017] [Indexed: 12/12/2022] Open
Abstract
Background: A compromised base excision repair (BER) promotes carcinogenesis by accumulating oxidative DNA-damaged products as observed in MUTYH-associated polyposis, a hereditary colorectal cancer syndrome marked by adenomas and cancers with an accumulation of 8-oxoguanine. Remarkably, DNA global demethylation has been shown to be mediated by BER, suggesting a relevant interplay with early colorectal tumourigenesis. To check this hypothesis, we investigated a cohort of 49 adenomas and 10 carcinomas, derived from 17 MUTYH-associated polyposis patients; as adenoma controls, we used a set of 36 familial adenomatous polyposis and 24 sporadic polyps. Methods: Samples were analysed for their mutational and epigenetic status, measured as global LINE-1 (long interspersed nuclear element) and gene-specific LINE-1 MET methylation by mass spectrometry and pyrosequencing. Results: MUTYH-associated polyposis adenomas were strikingly more hypomethylated than familial adenomatous and sporadic polyps for both DNA demethylation markers (P=0.032 and P=0.007 for LINE-1; P=0.004 and P<0.0001 for LINE-1 MET, respectively) with levels comparable to those of the carcinomas derived from the same patients. They also had mutations due mainly to KRAS/NRAS p.G12C, which was absent in the controls (P<0.0001 for both sets). Conclusions: Our results show that DNA demethylation, together with specific KRAS/NRAS mutations, drives the early steps of oxidative damage colorectal tumourigenesis.
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Affiliation(s)
- Daniela Furlan
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.,Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy
| | - Davide Trapani
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy
| | - Enrico Berrino
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy
| | - Carla Debernardi
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy
| | - Mara Panero
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy
| | - Laura Libera
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy
| | - Nora Sahnane
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy
| | - Cristina Riva
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.,Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy
| | - Maria Grazia Tibiletti
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy
| | - Fausto Sessa
- Anatomic Pathology Unit, Department of Surgical and Morphological Sciences, University of Insubria, Varese 21100, Italy.,Research Center for the Study of Hereditary and Familial Tumors, University of Insubria, Varese 21100, Italy
| | - Anna Sapino
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy
| | - Tiziana Venesio
- Molecular Pathology Laboratory, Unit of Pathology, Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142, Candiolo (Torino) 10060, Italy
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Lv XP. Gastrointestinal tract cancers: Genetics, heritability and germ line mutations. Oncol Lett 2017; 13:1499-1508. [PMID: 28454282 PMCID: PMC5403708 DOI: 10.3892/ol.2017.5629] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 11/21/2016] [Indexed: 12/18/2022] Open
Abstract
Gastrointestinal (GI) tract cancers that arise due to genetic mutations affect a large number of individuals worldwide. Even though many of the GI tract cancers arise sporadically, few of these GI tract cancers harboring a hereditary predisposition are now recognized and well characterized. These include Cowden syndrome, MUTYH-associated polyposis, hereditary pancreatic cancer, Lynch syndrome, Peutz-Jeghers syndrome, familial adenomatous polyposis (FAP), attenuated FAP, serrated polyposis syndrome, and hereditary gastric cancer. Molecular characterization of the genes that are involved in these syndromes was useful in the development of genetic testing for diagnosis and also facilitated understanding of the genetic basis of GI cancers. Current knowledge on the genetics of GI cancers with emphasis on heritability and germ line mutations forms the basis of the present review.
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Affiliation(s)
- Xiao-Peng Lv
- Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, The Affiliated Xuzhou Hospital of Medical College of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
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Hahn MM, de Voer RM, Hoogerbrugge N, Ligtenberg MJL, Kuiper RP, van Kessel AG. The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery. Cell Oncol (Dordr) 2016; 39:491-510. [PMID: 27279102 PMCID: PMC5121185 DOI: 10.1007/s13402-016-0284-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/27/2016] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5-10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes. CONCLUSIONS The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.
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Affiliation(s)
- M M Hahn
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - R M de Voer
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - N Hoogerbrugge
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - M J L Ligtenberg
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - R P Kuiper
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - A Geurts van Kessel
- Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
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