Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study
| Autor: | Tsun Leung Chan, Eugène T P Verwiel, Irma Kluijt, Diana Eccles, Rolf H. Sijmons, Egbert J.W. Redeker, Rachel S. van der Post, Encarna B. Gomez Garcia, Reinhard Büttner, Cora M. Aalfs, Roland P. Kuiper, Johan J.P. Gille, Bernadette P M van Nesselrooij, Frans B. L. Hogervorst, Marjolijn J L Ligtenberg, Tracy Graham, Julie O. Culver, Edith Olah, Monique Goossens, Carli M. J. Tops, Elke Holinski-Feder, David J. Bunyan, Marielle E. van Gijn, Frederik J. Hes, Suet Yi Leung, Pierre O. Chappuis, Monika Morak, Edward M Leter, Nils Rahner, Lea Velsher, János Papp, Renee C. Niessen, J. Han van Krieken, Lambertus A. Kiemeney, Ad Geurts van Kessel, Charlotte W. Ockeloen, Nicoline Hoogerbrugge, Marlies Kempers, Iris D. Nagtegaal, Verena Steinke, Hans K. Schackert, Matthias Kloor, Melanie R. Palomares, Sapna Syngal, Pierre Hutter, Elena M. Stoffel |
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| Přispěvatelé: | Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Clinical sciences, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Other Research, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Human genetics, CCA - Oncogenesis |
| Rok vydání: | 2011 |
| Předmět: |
Male
Oncology Genetics and epigenetic pathways of disease [NCMLS 6] REPAIR GENE HMSH2 Colorectal cancer FAMILIES chemistry.chemical_compound Promoter Regions Genetic Colorectal Neoplasms/etiology risk Sequence Deletion Medicine(all) METHYLATION Epithelial cell adhesion molecule Middle Aged Epithelial Cell Adhesion Molecule Translational research Tissue engineering and pathology [ONCOL 3] Lynch syndrome Antigens Neoplasm/genetics Endometrial Neoplasms/etiology MutS Homolog 2 Protein Cohort studies Female Duodenal cancer Colorectal Neoplasms Cell Adhesion Molecules/genetics STEM-CELLS MutS Homolog 2 Protein/genetics Adult medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Adolescent TACSTD1 Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1] MUTATION CARRIERS MLH1 Genomic disorders and inherited multi-system disorders [IGMD 3] Molecular epidemiology [NCEBP 1] Antigens Neoplasm Translational research [ONCOL 3] Internal medicine SURVEILLANCE medicine MANAGEMENT Humans Genetics and epigenetic pathways of disease Translational research [NCMLS 6] neoplasms Aged Molecular epidemiology Aetiology screening and detection [NCEBP 1] Gynecology Hereditary cancer and cancer-related syndromes [ONCOL 1] business.industry Endometrial cancer Cancer nutritional and metabolic diseases medicine.disease HYPERMETHYLATION digestive system diseases Endometrial Neoplasms MSH2 MSH6 chemistry business Cell Adhesion Molecules Gene Deletion |
| Zdroj: | Kempers, M J E, Kuiper, R P, Ockeloen, C W, Chappuis, P O, Hutter, P, Rahner, N, Schackert, H K, Steinke, V, Holinski-Feder, E, Morak, M, Kloor, M, Buttner, R, Verwiel, E T P, van Krieken, J H, Nagtegaal, I D, Goossens, M, van der Post, R S, Niessen, R C, Sijmons, RH, Kluijt, I, Hogervorst, F B L, Leter, E M, Gille, J J P, Aalfs, C M, Redeker, E J W, Hes, F J, Tops, C M J, van Nesselrooij, B P M, van Gijn, M E, Garcia, E B G, Eccles, D M, Bunyan, D J, Syngal, S, Stoffel, E M, Culver, J O, Palomares, M R, Graham, T, Velsher, L, Papp, J, Olah, E, Chan, T L, Leung, S Y, van Kessel, A G, Kiemeney, L A L M, Hoogerbrugge, N & Ligtenberg, M J L 2011, ' Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study ', Lancet Oncology, vol. 12, no. 1, pp. 49-55 . https://doi.org/10.1016/S1470-2045(10)70265-5 The Lancet Oncology, 49-55 STARTPAGE=49;ENDPAGE=55;TITLE=The Lancet Oncology Lancet Oncology, 12, 1, pp. 49-55 Lancet oncology, 12(1), 49-55. Elsevier Science Lancet Oncology, 12, 49-55 lancet oncology, 12(1), 49-55. Lancet Publishing Group Lancet Oncology, 12(1), 49-55. ELSEVIER SCIENCE INC Lancet Oncology, 12(1), 49-55. Lancet Publishing Group |
| ISSN: | 1470-2045 |
| Popis: | Summary Background Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6 , and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3′ end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM -expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions. Methods We obtained clinical data for 194 carriers of a 3′ end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6 , or a combined EPCAM–MSH2 deletion. Findings 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65–85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM–MSH2 deletion (69% [95% CI 47–91], p=0·8609) or mutations in MSH2 (77% [64–90], p=0·5892) or MLH1 (79% [68–90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38–62], p EPCAM deletions had a 12% [0–27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM–MSH2 deletion (55% [20–90], p MSH2 (51% [33–69], p=0·0006) or MSH6 (34% [20–48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15–51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer. Interpretation EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers. Funding Sacha Swarttouw-Hijmans Foundation, Dutch Cancer Society, Deutsche Krebshilfe (German Cancer Aid), Hong Kong Cancer Fund, Hungarian Research Grant OTKA, Norwegian EEA Financial Mechanism (Hungarian National Institute of Oncology), and US National Cancer Institute. |
| Databáze: | OpenAIRE |
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