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Nakagawa K, Sho M, Fujishiro M, Kakushima N, Horimatsu T, Okada KI, Iguchi M, Uraoka T, Kato M, Yamamoto Y, Aoyama T, Akahori T, Eguchi H, Kanaji S, Kanetaka K, Kuroda S, Nagakawa Y, Nunobe S, Higuchi R, Fujii T, Yamashita H, Yamada S, Narita Y, Honma Y, Muro K, Ushiku T, Ejima Y, Yamaue H, Kodera Y. Clinical practice guidelines for duodenal cancer 2021. J Gastroenterol 2022; 57:927-941. [PMID: 36260172 PMCID: PMC9663352 DOI: 10.1007/s00535-022-01919-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/03/2022] [Indexed: 02/07/2023]
Abstract
Duodenal cancer is considered to be a small intestinal carcinoma in terms of clinicopathology. In Japan, there are no established treatment guidelines based on sufficient scientific evidence; therefore, in daily clinical practice, treatment is based on the experience of individual physicians. However, with advances in diagnostic modalities, it is anticipated that opportunities for its detection will increase in future. We developed guidelines for duodenal cancer because this disease is considered to have a high medical need from both healthcare providers and patients for appropriate management. These guidelines were developed for use in actual clinical practice for patients suspected of having non-ampullary duodenal epithelial malignancy and for patients diagnosed with non-ampullary duodenal epithelial malignancy. In this study, a practice algorithm was developed in accordance with the Minds Practice Guideline Development Manual 2017, and Clinical Questions were set for each area of epidemiology and diagnosis, endoscopic treatment, surgical treatment, and chemotherapy. A draft recommendation was developed through a literature search and systematic review, followed by a vote on the recommendations. We made decisions based on actual clinical practice such that the level of evidence would not be the sole determinant of the recommendation. This guideline is the most standard guideline as of the time of preparation. It is important to decide how to handle each case in consultation with patients and their family, the treating physician, and other medical personnel, considering the actual situation at the facility (and the characteristics of the patient).
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Affiliation(s)
- Kenji Nakagawa
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Masayuki Sho
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
- Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan.
| | - Mitsuhiro Fujishiro
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Naomi Kakushima
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Takahiro Horimatsu
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Ken-Ichi Okada
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Mikitaka Iguchi
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Toshio Uraoka
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Motohiko Kato
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yorimasa Yamamoto
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Toru Aoyama
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Takahiro Akahori
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Hidetoshi Eguchi
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Shingo Kanaji
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kengo Kanetaka
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Shinji Kuroda
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yuichi Nagakawa
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Souya Nunobe
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Ryota Higuchi
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Tsutomu Fujii
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Hiroharu Yamashita
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Suguru Yamada
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yukiya Narita
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yoshitaka Honma
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Kei Muro
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Tetsuo Ushiku
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yasuo Ejima
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Hiroki Yamaue
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
| | - Yasuhiro Kodera
- The Japan Duodenal Cancer Guideline Committee, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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3
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Novel insights into molecular and immune subtypes of biliary tract cancers. Adv Cancer Res 2022; 156:167-199. [DOI: 10.1016/bs.acr.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Ota R, Sawada T, Tsuyama S, Sasaki Y, Suzuki H, Kaizaki Y, Hasatani K, Yamamoto E, Nakanishi H, Inagaki S, Tsuji S, Yoshida N, Doyama H, Minato H, Nakamura K, Kasashima S, Kubota E, Kataoka H, Tokino T, Yao T, Minamoto T. Integrated genetic and epigenetic analysis of cancer-related genes in non-ampullary duodenal adenomas and intramucosal adenocarcinomas. J Pathol 2020; 252:330-342. [PMID: 32770675 PMCID: PMC7693035 DOI: 10.1002/path.5529] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 07/20/2020] [Accepted: 07/28/2020] [Indexed: 12/24/2022]
Abstract
The molecular and clinical characteristics of non‐ampullary duodenal adenomas and intramucosal adenocarcinomas are not fully understood because they are rare. To clarify these characteristics, we performed genetic and epigenetic analysis of cancer‐related genes in these lesions. One hundred and seven non‐ampullary duodenal adenomas and intramucosal adenocarcinomas, including 100 small intestinal‐type tumors (90 adenomas and 10 intramucosal adenocarcinomas) and 7 gastric‐type tumors (2 pyloric gland adenomas and 5 intramucosal adenocarcinomas), were investigated. Using bisulfite pyrosequencing, we assessed the methylation status of CpG island methylator phenotype (CIMP) markers and MLH1. Then using next‐generation sequencing, we performed targeted exome sequence analysis within 75 cancer‐related genes in 102 lesions. There were significant differences in the clinicopathological and molecular variables between small intestinal‐ and gastric‐type tumors, which suggests the presence of at least two separate carcinogenic pathways in non‐ampullary duodenal adenocarcinomas. The prevalence of CIMP‐positive lesions was higher in intramucosal adenocarcinomas than in adenomas. Thus, concurrent hypermethylation of multiple CpG islands is likely associated with development of non‐ampullary duodenal intramucosal adenocarcinomas. Mutation analysis showed that APC was the most frequently mutated gene in these lesions (56/102; 55%), followed by KRAS (13/102; 13%), LRP1B (10/102; 10%), GNAS (8/102; 8%), ERBB3 (7/102; 7%), and RNF43 (6/102; 6%). Additionally, the high prevalence of diffuse or focal nuclear β‐catenin accumulation (87/102; 85%) as well as mutations of WNT pathway components (60/102; 59%) indicates the importance of WNT signaling to the initiation of duodenal adenomas. The higher than previously reported frequency of APC gene mutations in small bowel adenocarcinomas as well as the difference in the APC mutation distributions between small intestinal‐type adenomas and intramucosal adenocarcinomas may indicate that the adenoma–carcinoma sequence has only limited involvement in duodenal carcinogenesis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Ryosuke Ota
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Takeshi Sawada
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Sho Tsuyama
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasushi Sasaki
- Division of Biology, Department of Liberal Arts and Sciences, Center for Medical Education, Sapporo Medical University, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Yasuharu Kaizaki
- Department of Pathology, Fukui Prefectural Hospital, Fukui, Japan
| | - Kenkei Hasatani
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University, Sapporo, Japan
| | - Hiroyoshi Nakanishi
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Satoko Inagaki
- Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Shigetsugu Tsuji
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Naohiro Yoshida
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Hisashi Doyama
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Hiroshi Minato
- Department of Pathology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Keishi Nakamura
- Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Satomi Kasashima
- Department of Clinical Laboratory Science, Kanazawa University, Kanazawa, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Tokino
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshinari Minamoto
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
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Xue Y, Balci S, Aydin Mericoz C, Taskin OC, Jiang H, Pehlivanoglu B, Muraki T, Memis B, Saka B, Kim GE, Bandopadhyay S, Knight J, El-Rayes BF, Sarmiento J, Reid MD, Erkan M, Basturk O, Adsay V. Frequency and clinicopathologic associations of DNA mismatch repair protein deficiency in ampullary carcinoma: Routine testing is indicated. Cancer 2020; 126:4788-4799. [PMID: 32857459 DOI: 10.1002/cncr.33135] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 06/09/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The significance of DNA mismatch repair (MMR) deficiency in ampullary cancers (ACs) has not been established. METHODS In total, 127 ACs with invasive carcinomas measuring ≥3 mmthat had adequate tissue were analyzed immunohistochemically. RESULTS MMR loss was detected in 18% of ACs (higher than in colorectal cancers). Twelve tumors with MLH1-PMS2 loss were negative for BRAF V600E mutation, suggesting a Lynch syndrome association. MMR-deficient tumors (n = 23), comparedwith MMR-intact tumors (n = 104), showed a striking male predominance (male:female ratio, 4.7). Although the deficient tumors had slightly larger invasion size (2.7 vs 2.1 cm), they also had more expansile growth and less invasiveness, including less perineural invasion, and they ultimately had lower tumor (T) classification and less lymph node metastasis (30% vs 53%; P = .04). More important, patients who had MMR-deficient tumors had better clinical outcomes, with a 5-year overall survival rate of 68% versus 45% (P = .03), which was even more pronounced in those who had higher Tclassification (5-year overall survival, 69% vs 34%; P = .04). MMR deficiencyhad a statistically significant association with medullary phenotype, pushing-border invasion, and tumor-infiltrating immune cells, and it occurred more frequently in ampullary-duodenal type tumors. Programed cell death-ligand 1 (PD-L1) levels analyzed in the 22 MMR-deficient ACs revealed that all medullary carcinomas were positive. Nonmedullary MMR-deficient carcinomas expressed PD-L1 in 33% of tumors cells according to the criteria for a combined positive score ≥1, but all were negative according to the tumor proportion score≥1 method. CONCLUSIONS In ACs, MMR deficiency is even more frequent (18%) than in colon cancer and often has a Lynch-suggestive profile, thus routine testing is warranted. Male gender, pushing-border infiltration, ampullary-duodenal origin, medullary histology, and tumor-related inflammation have a significantly higher association with MMR deficiency. MMR-deficient tumors have less aggressive behavior. PD-L1 expression is common in medullary-phenotype ACs, thus immunotherapy should be considered at least for this group.
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Affiliation(s)
- Yue Xue
- Department of Pathology, Emory University, Atlanta, Georgia
| | - Serdar Balci
- Department of Pathology, Emory University, Atlanta, Georgia
| | - Cisel Aydin Mericoz
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
| | - Orhun C Taskin
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey
| | - Hongmei Jiang
- Department of Statistics, Northwestern University, Evanston, Illinois
| | | | - Takashi Muraki
- Department of Pathology, Emory University, Atlanta, Georgia
| | - Bahar Memis
- Department of Pathology, Emory University, Atlanta, Georgia
| | - Burcu Saka
- Department of Pathology, Emory University, Atlanta, Georgia
| | - Grace E Kim
- Department of Pathology, University of California San Francisco, San Francisco, California
| | | | - Jessica Knight
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Bassel F El-Rayes
- Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia
| | - Juan Sarmiento
- Department of Surgery, School of Medicine, Emory University, Atlanta, Georgia
| | | | - Mert Erkan
- Department of Surgery, Koç University School of Medicine, Istanbul, Turkey
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Volkan Adsay
- Department of Pathology, Koç University School of Medicine, Istanbul, Turkey.,Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
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Jun SY, Park ES, Lee JJ, Chang HK, Jung ES, Oh YH, Hong SM. Prognostic Significance of Stromal and Intraepithelial Tumor-Infiltrating Lymphocytes in Small Intestinal Adenocarcinoma. Am J Clin Pathol 2020; 153:105-118. [PMID: 31576398 DOI: 10.1093/ajcp/aqz136] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES Assessment of tumor-infiltrating lymphocytes (TILs) may predict the prognosis and therapeutic benefit of immunotherapy in small intestinal adenocarcinoma (SIAC) patients. METHODS TILs were evaluated in 231 surgically resected SIACs and compared with microsatellite instability (MSI) and clinicopathologic variables. The average number of intraepithelial TILs (iTILs) and the average density of stromal TILs (sTILs) were calculated separately. RESULTS High iTIL count (≥2 per high-power field) was associated with MSI-high, whereas high sTIL density (≥20% on ×200 magnification) was not. High iTIL count and high sTIL density were related to distal tumor location, medullary carcinoma, high Crohn-like lymphoid reaction counts, and fewer pancreatic invasions. SIAC patients with high iTIL count or high sTIL density had better survival than those with low values. On multivariate analysis, MSI, high sTIL density, proximal locations, lower N category, and absence of lymphovascular invasions and retroperitoneal seeding were the best independent prognostic predictors. CONCLUSIONS High sTIL density can be used as a prognostic indicator and high iTIL count may provide a basis for the clinical use of targeted immunotherapy in SIAC patients.
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Affiliation(s)
- Sun-Young Jun
- Department of Pathology, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Su Park
- Department of Pathology, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jae Jun Lee
- Department of Pathology, Good Morning Hospital, Pyeongtaek, Republic of Korea
| | - Hee-Kyung Chang
- Department of Pathology, Kosin University College of Medicine, Pusan, Republic of Korea
| | - Eun Sun Jung
- Department of Pathology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Ha Oh
- Department of Pathology, Hanyang University College of Medicine, Guri, Republic of Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Molecular alterations and PD-L1 expression in non-ampullary duodenal adenocarcinoma: Associations among clinicopathological, immunophenotypic and molecular features. Sci Rep 2019; 9:10526. [PMID: 31324814 PMCID: PMC6642201 DOI: 10.1038/s41598-019-46167-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 06/24/2019] [Indexed: 02/07/2023] Open
Abstract
Non-ampullary duodenal adenocarcinoma (NADC) is extremely rare. Little is known about its clinicopathological and molecular features or its management. Herein we retrospectively analyzed the cases of 32 NADC patients, focusing on microsatellite instability (MSI), genetic mutations, CpG island methylator phenotype (CIMP), and immunostaining including mucin phenotype and PD-L1 expression. The incidence of MSI, KRAS/BRAF/GNAS mutations and CIMP was 51.6%, 34.4%/3.1%/6.5% and 28.1%, respectively. PD-L1 expression was seen in 34.4% of patients. No significant associations between clinicopathological features and KRAS/BRAF/GNAS genetic mutations or CIMP were found. Histologically non-well-differentiated-type NADCs and those in the 1st portion of the duodenum were significantly associated with later stages (stages III–IV) (P = 0.006 and P = 0.003, respectively). Gastric-phenotype NADCs were frequently observed in the 1st portion and in late-stage patients; their cancer cells more frequently expressed PD-L1. Histologically, the non-well-differentiated type was an independent predictor of PD-L1 expression in cancer cells (OR 25.05, P = 0.04) and immune cells (OR 44.14, P = 0.02). Only late-stage disease (HR 12.23, P = 0.01) was a prognostic factor for worse overall survival in a Cox proportional hazards regression model. Our observation of high proportions of MSI and PD-L1 expression may prompt the consideration of immune checkpoint inhibitors as a new treatment option for NADCs.
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Jayaramayya K, Balachandar V, Santhy KS. Ampullary carcinoma-A genetic perspective. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 776:10-22. [PMID: 29807574 DOI: 10.1016/j.mrrev.2018.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 03/14/2018] [Accepted: 03/14/2018] [Indexed: 12/19/2022]
Abstract
Ampulla of vater carcinoma (AVC) is a rare gastrointestinal tumour that is associated with a high mortality rate and it's often diagnosed at later stages due to lack of clinical symptoms. Early diagnosis of this condition is essential to effectively treat patients for better prognosis. A significant amount of advancement has been made in understanding the molecular nature of cancer in the past decade. A substantial number of mutations and alterations have been detected in various tumors. Despite the occurrence of AVC across the globe, the number of studies conducted on this tumor type remains low; this is largely due to its rare occurrence. Moreover, AVC tissues are complex and contain mutations in oncogenes, tumour suppressors, apoptotic proteins, cell proliferation proteins, cell signaling proteins, transcription factors, chromosomal abnormalities and cellular adhesion proteins. The frequently mutated genes included KRAS, TP53 and SMAD4 and are associated with prognosis. Several molecules of the PI3K, Wnt signaling, TGF-beta pathway and cell cycle have also been altered in AVCs. This review comprises of all the genetic mutations, associated pathways and related prognosis that are involved in AVCs from the year 1989 to 2017. This report can be used as a stepping-stone to establish biomarkers for early diagnosis of AVC and to discover molecular targets for drug therapy.
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Affiliation(s)
- Kaavya Jayaramayya
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India.
| | - Vellingiri Balachandar
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India
| | - Kumaran Sivanandan Santhy
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women - Avinashilingam University for Women, Coimbatore 641 043, Tamil Nadu, India
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Knoblich N, Gundel F, Brückmann C, Becker-Sadzio J, Frischholz C, Nieratschker V. DNA methylation of APBA3 and MCF2 in borderline personality disorder: Potential biomarkers for response to psychotherapy. Eur Neuropsychopharmacol 2018; 28:252-263. [PMID: 29274998 DOI: 10.1016/j.euroneuro.2017.12.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 11/08/2017] [Accepted: 12/06/2017] [Indexed: 01/01/2023]
Abstract
Borderline personality disorder (BPD) is a severe and complex mental disease associated with high suicidal tendencies and hospitalization rates. Accumulating evidence suggests that epigenetic mechanisms are implicated in the etiology of BPD. A recent epigenome-wide study identified several novel genes which are epigenetically dysregulated in BPD. Those genes include APBA3 and MCF2. Psychotherapy such as Dialectical Behavior Therapy (DBT), an established treatment for BPD, provides an excellent setting to investigate environmental influences on epigenetic mechanisms in order to identify biomarkers for disease status and therapy success. However, the effects of DBT on epigenetic regulation has only been researched in one previous study analyzing BDNF. In the present study, we aimed to investigate the role of DNA methylation of APBA3 and MCF2 as possible biomarkers for treatment outcome in BPD, whilst validating the previous findings of differential DNA methylation in a cohort of 44 BPD patients and 44 well-matched healthy control individuals. Unexpectedly, we did not detect significant DNA methylation differences between patients and control individuals. However, we found a high correlation between the methylation status of APBA3 and MCF2 and therapy outcome: before DBT treatment, both genes were significantly higher methylated in patients responding to therapy compared to patients that did not respond. Our study is the first to report results pointing to possible predictive epigenetic biomarkers of DBT outcome in BPD patients. Following replication in independent cohorts, our finding could facilitate the development of more personalized therapy concepts for BPD patients by including epigenetic information.
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Affiliation(s)
- Nora Knoblich
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
| | - Friederike Gundel
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
| | - Christof Brückmann
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
| | - Julia Becker-Sadzio
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
| | - Christian Frischholz
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany
| | - Vanessa Nieratschker
- Department of Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany; Werner Reichardt Centre for Integrative Neuroscience, University of Tuebingen, Tuebingen, Germany.
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Yuza K, Nagahashi M, Watanabe S, Takabe K, Wakai T. Hypermutation and microsatellite instability in gastrointestinal cancers. Oncotarget 2017; 8:112103-112115. [PMID: 29340115 PMCID: PMC5762383 DOI: 10.18632/oncotarget.22783] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 11/13/2017] [Indexed: 02/07/2023] Open
Abstract
Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer. In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI). This review will focus on the frequency, characteristics and genomic signature of hypermutated gastrointestinal cancers with MSI. Detection of tumor hypermutation in cancer is expected to not only predict the clinical benefit of immune checkpoint inhibitor treatment, but also to provide better surgical strategies for the patients with hypermutated tumors. Thus, in an era of precision medicine, identification of hypermutation and MSI will play an important role directing surgical and chemotherapeutic treatment.
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Affiliation(s)
- Kizuki Yuza
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14203, USA
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
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Tewari M, Swain JR, Dixit VK, Shukla HS. Molecular Aberrations in Periampullary Carcinoma. Indian J Surg Oncol 2017; 8:348-356. [DOI: 10.1007/s13193-017-0645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 03/15/2017] [Indexed: 11/29/2022] Open
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Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma. PLoS One 2016; 11:e0162929. [PMID: 27643594 PMCID: PMC5028050 DOI: 10.1371/journal.pone.0162929] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 08/30/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. METHODS Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations. RESULTS MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups. CONCLUSIONS Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.
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The analysis of microsatellite instability in extracolonic gastrointestinal malignancy. Pathology 2014; 45:540-52. [PMID: 24018804 DOI: 10.1097/pat.0b013e3283653307] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Microsatellite instability (MSI) is a genetic feature of sporadic and familial cancers of multiple sites and is related to defective mismatch repair (MMR) protein function. Lynch syndrome (LS) is a familial form of MMR deficiency that may present with a spectrum of MSI positive cancers including gastrointestinal (GI) malignancies. The incidence of high level MSI (MSI-H) in colorectal carcinoma is well defined in both familial and sporadic cases and these tumours portend a better overall prognosis in colorectal carcinoma (CRC). There are certain morphological features that suggest MSI-H CRC and international guidelines have been established for the evaluation of MSI in CRC. The prevalence and morphological features of extracolonic GI MSI-H tumours are less well documented. Furthermore, it is unclear whether the guidelines for the assessment of MSI in CRC are appropriate for application to extracolonic GI malignancies. This review aims to summarise the recent literature on MSI in extracolonic LS-related GI tract malignancies with special attention to the assessment of the MMR system by evaluation of specific microsatellite markers and/or immunohistochemical evaluation of MMR protein expression. The reported prevalence of sporadic and LS-related MSI-H tumours along with their associated unique morphological patterns and related prognostic or therapeutic implications will be discussed.
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Kato N, Yamamoto H, Adachi Y, Ohashi H, Taniguchi H, Suzuki H, Nakazawa M, Kaneto H, Sasaki S, Imai K, Shinomura Y. Cancer detection by ubiquitin carboxyl-terminal esterase L1 methylation in pancreatobiliary fluids. World J Gastroenterol 2013; 19:1718-1727. [PMID: 23555160 PMCID: PMC3607748 DOI: 10.3748/wjg.v19.i11.1718] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 01/11/2013] [Accepted: 01/24/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the utility of measuring epigenetic alterations in pancreatic and biliary fluids in determining molecular markers for pancreatobiliary cancers.
METHODS: DNA was extracted from undiluted pancreatic and biliary fluids. As a surrogate for a genome-wide hypomethylation assay, levels of long interspersed nuclear element-1 (LINE-1) methylation were analyzed using bisulfite pyrosequencing. CpG island hypermethylation of 10 tumor-associated genes, aryl-hydrocarbon receptor repressor, adenomatous polyposis coli, calcium channel, voltage dependent, T type α1G subunit, insulin-like growth factor 2, O-6-methyl-guanine-DNA methyltransferase, neurogenin 1, CDKN2A, runt-related transcription factor 3 (RUNX3), secreted frizzled-related protein 1, and ubiquitin carboxyl-terminal esterase L1 (UCHL1), was analyzed using MethyLight. To examine the role of CpG methylation and histone deacetylation in the silencing of UCHL1, human gallbladder carcinoma cell lines and pancreatic carcinoma cell lines were treated with 2 or 5 μmol/L 5-AZA-dC for 72 h or 100 nmol/L Trichostatin A for 24 h. After the treatment, UCHL1 expression was analyzed by real-time reverse transcription-polymerase chain reaction.
RESULTS: Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease (58.7% ± 4.3% vs 61.7% ± 2.2%, P = 0.027; 53.8% ± 6.6% vs 57.5% ± 1.7%, P = 0.007); however, LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids (45.4% ± 5.5% vs 58.7% ± 4.3%, P < 0.001). CpG island hypermethylation of tumor-associated genes was detected at various frequencies, but it was not correlated with LINE-1 hypomethylation. Hypermethylation of the UCHL1 gene was cancer-specific and most frequently detected in pancreatic (67%) or biliary (70%) fluids from patients with pancreatobiliary cancer. As a single marker, hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancers, respectively (100% specificity). Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic (87% sensitivity and 100% specificity) and pancreatobiliary (97% sensitivity and 100% specificity) cancers. Treatment with a demethylating agent, 5-AZA-2’-deoxycytidine, restored UCHL1 expression in pancreatobiliary cancer cell lines.
CONCLUSION: Our results suggest that hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluid might be useful for the diagnosis of pancreatobiliary cancers.
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Fu T, Pappou EP, Guzzetta AA, Jeschke J, Kwak R, Dave P, Hooker CM, Morgan R, Baylin SB, Iacobuzio-Donahue CA, Wolfgang CL, Ahuja N. CpG island methylator phenotype-positive tumors in the absence of MLH1 methylation constitute a distinct subset of duodenal adenocarcinomas and are associated with poor prognosis. Clin Cancer Res 2012; 18:4743-52. [PMID: 22825585 DOI: 10.1158/1078-0432.ccr-12-0707] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE Little information is available on genetic and epigenetic changes in duodenal adenocarcinomas. The purpose was to identify possible subsets of duodenal adenocarcinomas based on microsatellite instability (MSI), DNA methylation, mutations in the KRAS and BRAF genes, clinicopathologic features, and prognosis. EXPERIMENTAL DESIGN Demographics, tumor characteristics, and survival were available for 99 duodenal adenocarcinoma patients. Testing for KRAS and BRAF mutations, MSI, MLH1 methylation, and CpG island methylator phenotype (CIMP) status was conducted. A Cox proportional hazard model was built to predict survival. RESULTS CIMP(+) was detected in 27 of 99 (27.3%) duodenal adenocarcinomas and was associated with MSI (P = 0.011) and MLH1 methylation (P < 0.001), but not with KRAS mutations (P = 0.114), as compared with CIMP(-) tumors. No BRAF V600E mutation was detected. Among the CIMP(+) tumors, 15 (55.6%) were CIMP(+)/MLH1-unmethylated (MLH1-U). Kaplan-Meier analysis showed that tumors classified by CIMP, CIMP/MLH1 methylation status, or CIMP/MSI status could predict overall survival (OS; P = 0.047, 0.002, and 0.002, respectively), whereas CIMP/MLH1 methylation status could also predict time-to-recurrence (TTR; P = 0.016). In multivariate analysis, CIMP/MLH1 methylation status showed a significant prognostic value in both OS (P < 0.001) and TTR (P = 0.023). Patients with CIMP(+)/MLH1-U tumors had the worst OS and TTR. CONCLUSIONS Our results showed existence of CIMP in duodenal adenocarcinomas. The combination of CIMP(+)/MLH1-U seems to be independently associated with poor prognosis in patients with duodenal adenocarcinomas. This study also suggests that BRAF mutations are not involved in duodenal tumorigenesis, MSI, or CIMP development.
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Affiliation(s)
- Tao Fu
- Department of Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
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Methylation of the calcium channel regulatory subunit α2δ-3 (CACNA2D3) predicts site-specific relapse in oestrogen receptor-positive primary breast carcinomas. Br J Cancer 2012; 107:375-81. [PMID: 22644305 PMCID: PMC3394973 DOI: 10.1038/bjc.2012.231] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background: Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer. Methods: We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α2δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions. Results: Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5′ regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system. Conclusion: Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.
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Shin SH, Lee K, Kim BH, Cho NY, Jang JY, Kim YT, Kim D, Jang JJ, Kang GH. Bile-based detection of extrahepatic cholangiocarcinoma with quantitative DNA methylation markers and its high sensitivity. J Mol Diagn 2012; 14:256-63. [PMID: 22446083 DOI: 10.1016/j.jmoldx.2012.01.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 11/15/2011] [Accepted: 01/04/2012] [Indexed: 12/15/2022] Open
Abstract
Extrahepatic cholangiocarcinoma (EHC) is usually difficult to diagnose by bile cytology because of cellular disintegration. However, DNA samples from bile fluid can provide sufficient materials to screen for the presence of EHC. We developed DNA methylation marker panels that can be used for MethyLight assay-based detection of EHC in bile fluid specimens. The methylation status of 59 DNA methylation markers was investigated in 20 EHC and 20 non-neoplastic gallbladder tissue samples with MethyLight assay to determine cancer-specific DNA methylation markers. Through assaying cancer-specific DNA methylation markers in a training set (n = 40) and validation set (n = 45) of bile fluid specimens from patients with EHC or those without cancer, we selected suitable marker panels that were assessed for their performance in a third set (test set; n = 40). Four marker panels showed a sensitivity of 60% or more and a specificity of 100% in both the training and validation sets, whereas bile cytology displayed a sensitivity of 40% to 46% and a specificity of 100%. In an independent test set of bile fluid samples, a five-gene panel (CCND2, CDH13, GRIN2B, RUNX3, and TWIST1) detected EHC at a sensitivity of 83%, which was far higher than that of bile cytology (46%, P = 0.004). Using bile fluids, a methylation assay consisting of a five-gene panel may be useful for detecting EHC and in helping to increase the sensitivity of preoperative diagnoses.
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Affiliation(s)
- So-Hyun Shin
- Laboratory of Epigenetics, Cancer Research Institute, Seoul, South Korea
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Su H, Hu N, Yang HH, Wang C, Takikita M, Wang QH, Giffen C, Clifford R, Hewitt SM, Shou JZ, Goldstein AM, Lee MP, Taylor PR, Kaempgen E, Van Gool SW, Helms W, Keegan P, Pazdur R. Global gene expression profiling and validation in esophageal squamous cell carcinoma and its association with clinical phenotypes. Clin Cancer Res 2011. [PMID: 29950348 DOI: 10.1158/1078-0432] [Citation(s) in RCA: 423] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy. EXPERIMENTAL DESIGN We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases by using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies. RESULTS A total of 159 genes showed differences with extreme statistical significance (P < E-15) and 2-fold differences or more in magnitude (tumor/normal RNA expression ratio, N = 53 cases), including 116 upregulated and 43 downregulated genes. Of 41 genes dysregulated in our prior array study, all but one showed the same fold change directional pattern in new array studies, including 29 with 2-fold changes or more. Alternative RNA expression methods validated array results: more than two thirds of 51 new cases examined by real-time PCR (RT-PCR) showed 2-fold differences or more for all seven genes assessed. Immunohistochemical protein expression results in 275 cases which were concordant with RNA for five of six genes. CONCLUSION We identified an expanded panel of genes dysregulated in ESCC and confirmed previously identified differentially expressed genes. Microarray-based gene expression results were confirmed by RT-PCR and protein expression studies. These dysregulated genes will facilitate molecular categorization of tumor subtypes and identification of their risk factors, and serve as potential targets for early detection, outcome prediction, and therapy.
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Affiliation(s)
- Hua Su
- Genetic Epidemiology Branch, DCEG, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Whitney Helms
- Office of Hematology and Oncology Products, Office of New Drugs, U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Patricia Keegan
- Office of Hematology and Oncology Products, Office of New Drugs, U.S. Food and Drug Administration, Silver Spring, Maryland
| | - Richard Pazdur
- Office of Biostatistics, Office of Translational Sciences, U.S. Food and Drug Administration, Silver Spring, Maryland
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Abstract
Aberrant DNA methylation in the genome is found in almost all types of cancer and contributes to malignant transformation by silencing multiple tumour-suppressor genes, sometimes simultaneously. Therefore, deciphering the signature of DNA methylation in each tumour is required to better understand tumour behaviour and might be of benefit for clinical diagnostics and therapy. Recent technologies for high-throughput genome-wide DNA methylation analyses are promising and potent tools for epigenetic profiling. Since epigenetic therapy is now in clinical use or trials for several types of cancers, efficient epigenetic profiling is required. In this review, the current key technologies available to assess genome-wide DNA methylation are introduced and the implications of DNA methylation profiling in human cancers are discussed.
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Diosdado B, Buffart TE, Watkins R, Carvalho B, Ylstra B, Tijssen M, Bolijn AS, Lewis F, Maude K, Verbeke C, Nagtegaal ID, Grabsch H, Mulder CJJ, Quirke P, Howdle P, Meijer GA. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res 2010; 16:1391-401. [PMID: 20179237 DOI: 10.1158/1078-0432.ccr-09-1773] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment. EXPERIMENTAL DESIGN Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas. RESULTS DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable. CONCLUSIONS Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401.
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Affiliation(s)
- Begoña Diosdado
- Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.
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García P, Manterola C, Araya JC, Villaseca M, Guzmán P, Sanhueza A, Thomas M, Alvarez H, Roa JC. Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. Mol Carcinog 2009; 48:79-89. [DOI: 10.1002/mc.20457] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Immunohistochemical and molecular features of sporadic and FAP-associated duodenal adenomas of the ampullary and nonampullary mucosa. Am J Surg Pathol 2008; 32:1388-95. [PMID: 18670349 DOI: 10.1097/pas.0b013e3181723679] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The pathogenesis of duodenal adenomas is not well elucidated. Much of the literature pertains to ampullary adenomas and those associated with familial adenomatous polyposis (FAP). In this study, we evaluated the molecular features of a series of sporadic duodenal adenomas (n=22) that developed distal to the ampulla, and compared them with the features of sporadic ampullary adenomas (n=9) and FAP-related polyps (n=12). Using a combination of immunohistochemical studies [cytokeratins 7 and 20, E-cadherin, beta-catenin, p53, MLH-1, MSH-2, MSH-6, and O6-methylguanine methyltransferase (MGMT)], DNA sequencing [beta-catenin, adenomatous polyposis coli (APC), p53, KRAS, and BRAF], and a polymerase chain reaction-based microsatellite instability assay; we assessed each case for abnormalities in the Wnt signaling and mitogen-activated protein kinase pathways and DNA repair mechanisms. Wnt signaling pathway abnormalities occurred in sporadic, nonampullary (82%), and ampullary (77%) adenomas at comparable rates, usually reflecting nuclear beta-catenin immunostaining (64% and 44%, respectively), and APC rather than beta-catenin, mutations. KRAS mutations were infrequent in sporadic, nonampullary adenomas (18%), and FAP-related adenomas (9%); moderately frequent in ampullary adenomas (44%); and none of the cases harbored BRAF mutations. Only 4 (13%) sporadic adenomas showed nuclear p53 staining, but no p53 mutations were detected in exons 5 to 8. Loss of O-methylguanine methyltransferase immunostaining was identified in 1 sporadic, nonampullary adenoma, and none of the polyps in any group showed loss of MLH-1, MSH-2, or MSH-6 staining, or high-frequency microsatellite instability. We conclude that sporadic and FAP-related adenomas show similar molecular features, regardless of their anatomic location. Similar to colorectal adenomas, they harbor APC and KRAS mutations; but BRAF mutations, p53 alterations, and DNA mismatch repair abnormalities are rare.
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Suehiro Y, Okada T, Okada T, Anno K, Okayama N, Ueno K, Hiura M, Nakamura M, Kondo T, Oga A, Kawauchi S, Hirabayashi K, Numa F, Ito T, Saito T, Sasaki K, Hinoda Y. Aneuploidy predicts outcome in patients with endometrial carcinoma and is related to lack of CDH13 hypermethylation. Clin Cancer Res 2008; 14:3354-61. [PMID: 18519763 DOI: 10.1158/1078-0432.ccr-07-4609] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Many investigators have reported that aneuploidy detected by flow cytometry is a useful prognostic marker in patients with endometrial cancer. Laser scanning cytometry (LSC) is a technology similar to flow cytometry but is more feasible for clinical laboratory use. We evaluated the usefulness of DNA ploidy detected by LSC as a prognostic marker in patients with endometrial cancer and investigated genetic and epigenetic factors related to aneuploidy. EXPERIMENTAL DESIGN Endometrial cancer specimens from 106 patients were evaluated. The methylation status of CDH13, Rassf1, SFRP1, SFRP2, SFRP4, SFRP5, p16, hMLH1, MGMT, APC, ATM, and WIF1 and mutations in the p53 and CDC4 genes were investigated. LSC was carried out to determine DNA ploidy. Fluorescence in situ hybridization was done with chromosome-specific centromeric probes to assess chromosomal instability. RESULTS Univariate and multivariate analyses revealed that p53 mutation and lack of CDH13 hypermethylation associated positively with aneuploidy. Univariate analysis showed that aneuploidy, chromosomal instability, and lack of CDH13 hypermethylation as well as surgical stage were significantly predictive of death from endometrial cancer. Furthermore, multivariate analysis revealed that stage in combination with either DNA aneuploidy or lack of CDH13 hypermethylation was an independent prognostic factor. CONCLUSION These results suggest that analysis of DNA ploidy and methylation status of CDH13 may help predict clinical outcome in patients with endometrial cancer. Prospective randomized trials are needed to confirm the validity of an individualized approach, including determination of tumor ploidy and methylation status of CDH13, to management of endometrial cancer patients.
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Affiliation(s)
- Yutaka Suehiro
- Department of Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
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CpG island methylator phenotype (CIMP) in cancer: causes and implications. Cancer Lett 2008; 268:177-86. [PMID: 18471961 DOI: 10.1016/j.canlet.2008.03.022] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2008] [Revised: 03/19/2008] [Accepted: 03/19/2008] [Indexed: 12/31/2022]
Abstract
Strong evidence exists for a subgroup of tumours, from a variety of tissue types, exhibiting concordant tumour specific DNA methylation: the "CpG island methylator phenotype" (CIMP). Occurrence of CIMP is associated with a range of genetic and environmental factors, although the molecular causes are not well-understood. Both increased expression and aberrant targeting of DNA methyltransferases (DNMTs) could contribute to the occurrence of CIMP. One under-explored area is the possibility that DNA damage may induce or select for CIMP during carcinogenesis or treatment of tumours with chemotherapy. DNA damaging agents can induce DNA damage at guanine rich regions throughout the genome, including CpG islands. This DNA damage can result in stalled DNA synthesis, which will lead to localised increased DNMT1 concentration and therefore potentially increased DNA methylation at these sites. Chemotherapy can select for cells which have increased tolerance to DNA damage due to increased lesion bypass, in some cases by mechanisms which involve inactivation of genes by CpG island methylation. CIMP has been associated with worse patient prognosis, probably due to increased epigenetic plasticity. Therefore, further clinical testing of the diagnostic and prognostic value of the current CIMP markers, as well as increasing our understanding of the molecular causes underlying CIMP are required.
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Berkhout M, Nagtegaal ID, Cornelissen SJB, Dekkers MMG, van de Molengraft FJJM, Peters WHM, Nagengast FM, van Krieken JHJM, Jeuken JWM. Chromosomal and methylation alterations in sporadic and familial adenomatous polyposis-related duodenal carcinomas. Mod Pathol 2007; 20:1253-62. [PMID: 17873900 DOI: 10.1038/modpathol.3800952] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Primary carcinomas of the small intestine are rare and the mechanism of their pathogenesis is poorly understood. Patients with familial adenomatous polyposis (FAP) have a high risk of developing duodenal carcinomas. The aim of this study is to gain more insight into the development of duodenal carcinomas. Therefore, five FAP-related duodenal carcinomas were characterized for chromosomal and methylation alterations, which were compared to those observed in sporadic duodenal carcinomas. Comparative genomic hybridization (CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed in 10 primary sporadic and five primary FAP-related duodenal carcinomas. In the FAP-related carcinomas, frequent gains were observed on chromosomes 8, 17 and 19, whereas in sporadic carcinomas they occurred on chromosomes 8, 12, 13 and 20. In 60% of the sporadic carcinomas, gains in the regions of chromosome 12 were observed which were absent in the FAP-related carcinomas (P=0.04). Hypermethylation was observed in the immunoglobulin superfamily genes member 4 (IGSF4), TIMP metallopeptidase inhibitor 3 (TIMP3), Estrogen receptor 1 (ESR1), adenomatous polyposis coli (APC), H-cadherin (CDH13) and paired box gene 6 (PAX6) genes. Hypermethylation of PAX6 was only observed in FAP-related carcinomas (3/5) and not in sporadic carcinomas (P=0.02). In conclusion, in contrast to sporadic duodenal carcinomas, gains on chromosome 12 were not observed in duodenal carcinomas of patients with FAP. Identification of the genes in these regions of chromosome 12 could lead to a better understanding of the carcinogenesis pathways leading to sporadic and FAP-related duodenal carcinomas. Furthermore, hypermethylation seems to be a general feature of both FAP-related duodenal carcinomas as well as sporadic duodenal carcinomas with the exception of the PAX6 gene, which is methylated only in FAP-related carcinomas.
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Affiliation(s)
- Marloes Berkhout
- Department of Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
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Abstract
Ca2+ is a ubiquitous cellular signal. Altered expression of specific Ca2+ channels and pumps are characterizing features of some cancers. The ability of Ca2+ to regulate both cell death and proliferation, combined with the potential for pharmacological modulation, offers the opportunity for a set of new drug targets in cancer. However, the ubiquity of the Ca2+ signal is often mistakenly presumed to thwart the specific therapeutic targeting of proteins that transport Ca2+. This Review presents evidence to the contrary and addresses the question: which Ca2+ channels and pumps should be targeted?
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Affiliation(s)
- Gregory R Monteith
- School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia, 4072.
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Kim BH, Cho NY, Choi M, Lee S, Jang JJ, Kang GH. Methylation profiles of multiple CpG island loci in extrahepatic cholangiocarcinoma versus those of intrahepatic cholangiocarcinomas. Arch Pathol Lab Med 2007; 131:923-30. [PMID: 17550320 DOI: 10.5858/2007-131-923-mpomci] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2006] [Indexed: 01/16/2023]
Abstract
CONTEXT CpG island hypermethylation is attracting attention because of its importance as a tumor marker and its potential mechanism for the development of human cancers. Extrahepatic cholangiocarcinoma has been poorly investigated with respect to CpG island hypermethylation, and the number of genes known to be methylated in extrahepatic cholangiocarcinomas is fewer than 20. OBJECTIVE To generate methylation profiles of 24 CpG island loci in extrahepatic cholangiocarcinomas, to correlate methylation findings with clinicopathologic findings, and to compare these findings with those of intrahepatic cholangiocarcinomas. DESIGN Sixty-three extrahepatic cholangiocarcinomas and 48 intrahepatic cholangiocarcinomas were investigated for hypermethylation in 24 CpG island loci by using methylation-specific polymerase chain reaction. RESULTS A total of 61 (96.8%) of 63 extrahepatic cholangiocarcinomas showed hypermethylation in at least one of the examined loci, and a high methylation frequency was seen in HOXA1 (95.2%), HPP1 (69.8%), and NEUROG1 (61.9%). The number of methylated CpG island loci was greater in extrahepatic cholangiocarcinomas with nodal metastasis than in those without nodal metastasis (P = .047), and hypermethylation of TIG1 was closely associated with nodal metastasis of extrahepatic cholangiocarcinomas (P = .007). CDH1 and NEUROG1 were more frequently methylated in extrahepatic cholangiocarcinoma than in intrahepatic cholangiocarcinoma, whereas CHFR, GSTP1, IGF2, MGMT, MINT31, p14, and RBP1 were more frequently methylated in intrahepatic cholangiocarcinoma: the differences was statistically significant (P < .05). CONCLUSIONS A close relationship exists between CpG island hypermethylation and nodal metastasis of extrahepatic cholangiocarcinomas. Methylation profiles of extrahepatic cholangiocarcinomas are somewhat similar to but distinct from those of intrahepatic cholangiocarcinomas.
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Affiliation(s)
- Baek-Hee Kim
- Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744 South Korea
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28
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Chang MC, Chang YT, Sun CT, Chiu YF, Lin JT, Tien YW. Differential Expressions of Cyclin D1 Associated with Better Prognosis of Cancers of Ampulla of Vater. World J Surg 2007; 31:1135-41. [PMID: 17420962 DOI: 10.1007/s00268-006-0032-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
BACKGROUND Periampullary cancers, the incidence of which increases gradually with industrialization, still pose a significant challenge to clinicians and researchers. Specifically, the role of cell-cycle proteins and tumor suppressor genes in these cancers is not yet clear. Recent studies have revealed that genes and proteins related to cell cycle and apoptosis regulation may be involved in pancreatic carcinogenesis. METHODS Tissue samples were obtained from patients with periampullary cancers who underwent surgery at the National Taiwan University Hospital without receiving previous chemotherapy or radiation therapy. All periampullary cancer tissue samples were examined by a pathologist, who was unaware of the parameters to be investigated. A total of 68 patients with periampullary cancers (29 ampulla of Vater cancers (AVCs) and 39 pancreatic ductal cancers (PDCs), including various stages and histological subtypes, were enrolled. The relevant demographic and clinicopathological information was obtained from medical records. RESULTS Cell-cycle proteins, including p16, Rb, cyclin D1, p53, and E2F1, were analyzed by immunohistochemical staining. Here, significant differences were noted between AVCs and PDCs with regard to the expression of cyclin D1. This corresponded to a poor prognosis in PDCs (P < 0.05); AVCs, on the other hand, showed a relatively high survival rate. There is no obvious statistical difference between the 2 groups with regard to the expression of p16, Rb, p53, and E2F1. The study also revealed that cyclin D1 plays different roles in the carcinogenesis of AVCs and PDCs. CONCLUSIONS The expression of cyclin D1 is more often correlated with prognosis in AVCs than in PDCs, and may serve as a biomarker for the disease.
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Affiliation(s)
- Ming-Chug Chang
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, No. 7, Chung-Shan, South Road, Taipei, Taiwan, ROC
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Kohya N, Koga Y, Kitajima Y, Miyazaki K. Aberrant promoter hypermethylation in biliary tract carcinoma. ACTA ACUST UNITED AC 2006; 13:296-305. [PMID: 16858540 DOI: 10.1007/s00534-005-1058-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2005] [Accepted: 09/01/2005] [Indexed: 10/24/2022]
Abstract
Biliary tract carcinoma is a relatively rare tumor with a poor survival rate. The molecular biological mechanisms underlying the development of biliary tract carcinomas are not well understood. Promoter methylation is an important epigenetic mechanism for suppressing tumor-suppressor gene activity. There is limited information regarding the abnormal methylation of cancer-related genes in biliary tract carcinoma; however, a few insights have been obtained into the role of epigenetic silencing in the progression of biliary tract carcinoma. In this review, we summarize recent data on gene silencing by promoter hypermethylation, and we discuss the implications for biliary tract carcinomas.
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Affiliation(s)
- Naohiko Kohya
- Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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Brücher BLDM, Geddert H, Langner C, Höfler H, Fink U, Siewert JR, Sarbia M. Hypermethylation ofhMLH1,HPP1,p14ARF,p16INK4A andAPC in primary adenocarcinomas of the small bowel. Int J Cancer 2006; 119:1298-302. [PMID: 16619216 DOI: 10.1002/ijc.21990] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Small bowel adenocarcinoma (SB-AC) is a very rare tumor entity. Epigenetic alterations, including hypermethylation of DNA mismatch repair genes and tumor suppressor genes, seem to be important for carcinogenesis in tumors of the gastrointestinal tract, but have not yet been investigated in SB-AC. In the current study, the prevalence of hypermethylation in a panel of genes involved in gastrointestinal carcinogenesis (hMLH1, HPP1, p14(ARF), p16(INK4A), APC) was determined in a series of SB-AC. Paraffin-embedded tumor samples from 56 patients with SB-AC who underwent surgical resection between January 1985 and December 2003 were investigated for hypermethylation by means of methylation-specific real-time PCR, and compared with our findings in a previously investigated series of 50 gastric adenocarcinomas. In comparison with adenocarcinomas of the stomach, SB-AC revealed a significantly higher rate of hypermethylation of HPP1 (86% versus 54%, p = 0.0003), p16(INK4A) (32% versus 10%, p = 0.0006), and a significantly lower rate of hypermethylation of APC (48% versus 84%, p = 0.0001). Hypermethylation of hMLH1 and p14(ARF) was present in 23% and 9% of SB-AC, respectively. Locally advanced tumor categories (pT3/4) showed a higher rate of hypermethylation of HPP1 (90%) than did early tumor categories (pT1/2 categories, 40%; p = 0.0036). This was also reflected by the correlation between the HPP1 hypermethylation and high UICC stage (p = 0.02). No correlation was found between hypermethylation and other clinicopathologic parameters such as age, tumor grade and nodal status. Our findings suggest that hypermethylation of hMLH1, HPP1, p16(INK4A) and APC is frequent in primary adenocarcinomas of the small bowel. The differences in the hypermethylation spectrum of small bowel and stomach cancer indicate significant epigenetic differences between these tumors.
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Affiliation(s)
- Björn L D M Brücher
- Department of Surgery, Technical University of Munich, Ismaninger Strasse 22, D-81675 Munich, Germany.
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Matsubayashi H, Sato N, Brune K, Blackford AL, Hruban RH, Canto M, Yeo CJ, Goggins M. Age- and Disease-Related Methylation of Multiple Genes in Nonneoplastic Duodenum and in Duodenal Juice. Clin Cancer Res 2005. [DOI: 10.1158/1078-0432.573.11.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Abstract
Purpose: Methylation of CpG islands contributes to gene silencing during cancer development, and although some methylation alterations are promising diagnostic markers of cancer, some CpG islands are also methylated in normal tissues. We have previously observed that some normally unmethylated CpG islands that undergo methylation in pancreatic cancers are normally methylated in the adjacent duodenum. Because duodenal methylation patterns are an important consideration when sampling pancreatic tissues for pancreatic cancer methylation alterations, we determined the DNA methylation patterns of 24 genes in the normal duodenum of patients with pancreatic disease and related these patterns to demographic factors.
Experimental Design: The nonneoplastic duodenal mucosa of 158 patients with pancreatic carcinoma and 41 patients with chronic pancreatitis was analyzed using methylation-specific PCR and combined bisulfite restriction analysis. Secretin-stimulated pancreatic/duodenal juice from 15 individuals undergoing endoscopic investigation for upper gastrointestinal disease was also analyzed.
Results: Low-level methylation was detectable by methylation-specific PCR in the nonneoplastic duodenum of many patients with pancreatic cancer and chronic pancreatitis as well as in the pancreaticoduodenal secretions of patients without pancreaticobiliary disease. For many genes, the prevalence of methylation increased with age and was more prevalent in patients with pancreatic cancer than in age-matched patients with chronic pancreatitis.
Our results indicate that strategies to detect pancreatic cancer using aberrantly methylated genes should rely on analysis of pure pancreatic juice rather than on pancreatic juice collected within the duodenal lumen. Patients who develop pancreatic cancer may have a greater propensity to methylate CpG islands than age-matched controls.
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Affiliation(s)
- Hiroyuki Matsubayashi
- 1Pathology, Departments of
- 6Fourth Department of Internal Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
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Frigola J, Solé X, Paz MF, Moreno V, Esteller M, Capellà G, Peinado MA. Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer. Hum Mol Genet 2004; 14:319-26. [PMID: 15574462 DOI: 10.1093/hmg/ddi028] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cancer cells are characterized by a generalized disruption of the DNA methylation pattern involving an overall decrease in the level of 5-methylcytosine together with regional hypermethylation of particular CpG islands. The extent of both DNA hypomethylation and hypermethylation in the tumor cell is likely to reflect distinctive biological and clinical features, although no studies have addressed its concurrent analysis until now. DNA methylation profiles in sporadic colorectal carcinomas, synchronous adenoma-carcinoma pairs and their matching normal mucosa were analyzed by using the amplification of inter-methylated sites (AIMS) method. A total of 208 AIMS generated sequences were tagged and evaluated for differential methylation. Global indices of hypermethylation and hypomethylation were calculated. All tumors displayed altered patterns of DNA methylation in reference to normal tissue. On average, 24% of the tagged sequences were differentially methylated in the tumor in regard to the normal pair with an overall prevalence of hypomethylations to hypermethylations. Carcinomas exhibited higher levels of hypermethylation than did adenomas but similar levels of hypomethylation. Indices of hypomethylation and hypermethylation showed independent correlations with patient's sex, tumor staging and specific gene hypermethylation. Hierarchical cluster analysis revealed two main patterns of DNA methylation that were associated to particular mutational spectra in the K-ras and the p53 genes and alternative correlates of hypomethylation and hypermethylation with survival. We conclude that DNA hypermethylation and hypomethylation are independent processes and appear to play different roles in colorectal tumor progression. Subgroups of colorectal tumors show specific genetic and epigenetic signatures and display distinctive correlates with overall survival.
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Affiliation(s)
- Jordi Frigola
- IDIBELL-Institut de Recerca Oncològica, L'Hospitalet, Barcelona, Spain
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Abstract
PURPOSE OF REVIEW Biliary tract neoplasm is one of the most aggressive malignancies, with a very poor prognosis. Most cancers of the biliary tract will have grown beyond the limits of curative resection by the time they become clinically evident. This reality has fostered therapeutic nihilism, and most physicians and surgeons, in their pessimism, have to run ambitious trials evaluating new diagnostic tools and therapeutic techniques in this disease. RECENT FINDINGS Advances in imaging over the period of the last 5 years now allow for earlier diagnosis and better surgical planning. Recent improvements in operative technique have substantially improved the outlook of patients with this cancer. Palliative management of obstructive disease recently has been improved with the advent of photodynamic therapy. Among the different drugs tested in this disease, gemcitabine seems to have the best efficacy:toxicity ratio. However, efficacy results remain disappointing, and combination schedules need to be developed to improve the results. Among them, the gemcitabine-oxaliplatin combination seems to be one of the most promising schedules. Biological studies, especially those evaluating mutation-independent activation of the Hedgehog pathway, have provided interesting information on the carcinogenesis of this rare tumor. Furthermore, these results bring us the opportunity of development of future targeted therapies in biliary tract cancer. SUMMARY Biliary tract neoplasm remains one of the most aggressive malignancies. However, as for other gastrointestinal malignancies, biological studies and diagnostic and therapeutic improvements have provided interesting results that could lead to a major improvement in the prognosis of this disease.
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Affiliation(s)
- David Malka
- Unité de Gastroentérologie, Institut Gustave Roussy, Villejuif, France
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Abstract
Fifteen years after the first demonstration of epigenetic tumor-suppressor gene inactivation associated with promoter methylation, the field has reached a level of understanding that threatens a re-writing of established biologic concepts. In gastrointestinal malignancies, epigenetic analysis has led to novel hypotheses regarding the etiology of age-associated cancer susceptibility and the interactions between environmental exposures and neoplasia. Methylation profiling has uncovered a distinct pathway to colorectal neoplasia that may arise from a hitherto underestimated precursor lesion, the proximal hyperplastic polyp-serrated adenoma pathway. Epigenetic information has shown promise in clarifying susceptibility to cancer and defining poor prognosis groups in gastrointestinal cancers. Finally, the field has engendered renewed interest in therapeutic targeting of epigenetic regulatory molecules, and several such drugs are currently in clinical trials. It is likely that epigenetic pathways will be integrated in the routine management of gastrointestinal malignancies over the next decade.
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Affiliation(s)
- Asif Rashid
- Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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Tozawa T, Tamura G, Honda T, Nawata SI, Kimura W, Makino N, Kawata S, Sugai T, Suto T, Motoyama T. Promoter hypermethylation of DAP-kinase is associated with poor survival in primary biliary tract carcinoma patients. Cancer Sci 2004; 95:736-40. [PMID: 15471559 PMCID: PMC11159369 DOI: 10.1111/j.1349-7006.2004.tb03254.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
To clarify the clinicopathological significance of promoter hypermethylation of tumor suppressor and tumor-related genes in biliary tract carcinomas, we examined the promoter methylation status of multiple genes in primary biliary tract carcinomas. These consisted of carcinomas of the bile duct, gallbladder, and duodenal ampulla. Surgical specimens were obtained from a total of 37 patients with biliary tract carcinoma. The cohort consisted of 23 patients with bile duct carcinoma, 9 patients with gallbladder carcinoma, and 5 patients with ampullary carcinoma. The methylation status of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 was examined by methylation-specific polymerase chain reaction (MSP). The correlation between methylation status and clinicopathological characteristics was then assessed. The methylation frequencies of CHFR, DAP-kinase, E-cadherin, hMLH1, p16, RASSF1A, and RUNX3 genes were 16.2%, 21.4%, 27.0%, 8.1%, 24.3%, 27.0%, and 56.8%, respectively, in primary biliary tract carcinomas. The number of methylated genes per sample was 2.17 +/- 0.28 (average +/- SD) in bile duct carcinomas, 1.80 +/- 0.97 in ampullary carcinomas, and 0.89 +/- 0.35 in gallbladder carcinomas, with a statistically significant difference between bile duct carcinomas and gallbladder carcinomas (P = 0.02). As for clinicopathological significance, patients with a methylated RUNX3 promoter were significantly older than those with unmethylated RUNX3 (P = 0.01), and DAP-kinase methylation was more frequent in poorly differentiated tumors than in well to moderately differentiated ones (P = 0.04). The overall survival rate was significantly lower in patients with methylated DAP-kinase (P = 0.009) or RUNX3 (P = 0.034) compared to those with unmethylated genes. Furthermore, DAP-kinase methylation-positive status was independently associated with poor survival in multivariate analyses (hazard ratio = 8.71, P = 0.024). A significant proportion of primary biliary tract carcinomas exhibited promoter hypermethylation of tumor suppressor and tumor-related genes, although bile duct carcinomas are more prone to being affected by promoter methylation than are gallbladder carcinomas. Hypermethylation of DAP-kinase appears to be a significant prognostic factor in primary biliary tract carcinomas.
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Affiliation(s)
- Tomohiro Tozawa
- Department of Pathology, Yamagata University School of Medicine, Yamagata 990-9585, Japan
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Lofton-Day C, Lesche R. DNA methylation markers in patients with gastrointestinal cancers. Current understanding, potential applications for disease management and development of diagnostic tools. Dig Dis 2003; 21:299-308. [PMID: 14752219 DOI: 10.1159/000075352] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
DNA methylation, the modification of a cytosine nucleotide immediately preceding a guanine base in a stretch of DNA, is rapidly gaining strength in the diagnostic field as a powerful tool to be utilized for the discrimination of neoplastic tissue from its healthy counterpart. This epigenetic modification occurs often in the promoter region of genes and is associated with transcriptional silencing of tumor suppressors or other genes important for normal cellular function. These changes have been found to occur at very early stages in the progression of healthy to malignant phenotype in many cancer types. We are taking a targeted approach to finding methylation-based markers that can be used not only for the early detection of cancer but also for determining risk, monitoring patient response to therapy and even determining the degree of aggressiveness of a tumor. In this paper, we review the progress in our understanding of methylation in gastrointestinal tumors, the potential clinical applications of methylation-based markers and our process for the discovery and validation of highly specific and sensitive markers for the use in these applications.
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