Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome

Genes Chromosomes and Cancer - Tập 48 Số 8 - Trang 737-744 - 2009
Renée C. Niessen1, Robert M.W. Hofstra1, Helga Westers1, Marjolijn J.L. Ligtenberg2, Krista Kooi1, Paul O. J. Jager1, Marloes L. de Groote1, Trijnie Dijkhuizen1, Maran J.W. Olderode-Berends1, Harry Hollema3, Jan H. Kleibeuker4, Rolf H. Sijmons4
1Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
2Department of Human Genetics and Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
3Targeted Gynaecologic Oncology (TARGON)
4Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Tóm tắt

AbstractIt was shown that Lynch syndrome can be caused by germline hypermethylation of the MLH1 and MSH2 promoters. Furthermore, it has been demonstrated very recently that germline deletions of the 3′ region of EPCAM cause transcriptional read‐through which results in silencing of MSH2 by hypermethylation. We wanted to determine the prevalence of germline MLH1 promoter hypermethylation and of germline and somatic MSH2 promoter hypermethylation in a large group of Lynch syndrome‐suspected patients. From a group of 331 Lynch Syndrome‐suspected patients we selected cases, who had no germline MLH1, MSH2, or MSH6 mutation and whose tumors showed loss of MLH1 or MSH2, or, if staining was unavailable, had a tumor with microsatellite instability. Methylation assays were performed to test these patients for germline MLH1 and/or MSH2 promoter hypermethylation. Two patients with germline MLH1 promoter hypermethylation and no patients with germline MSH2 promoter hypermethylation were identified. In the subgroup screened for germline MSH2 promoter hypermethylation, we identified 3 patients with somatic MSH2 promoter hypermethylation in their tumors, which was caused by a germline EPCAM deletion. In the group of 331 Lynch Syndrome‐suspected patients, the frequencies of germline MLH1 promoter hypermethylation and somatic MSH2 promoter hypermethylation caused by germline EPCAM deletions are 0.6 and 0.9%, respectively. These mutations, therefore, seem to be rather infrequent. However, the contribution of germline MLH1 hypermethylation and EPCAM deletions to the genetically proven Lynch syndrome cases in this cohort is very high. Previously 27 pathogenic mutations were identified; the newly identified mutations now represent 16% of all mutations. © 2009 Wiley‐Liss, Inc.

Từ khóa


Tài liệu tham khảo

10.1126/science.8484121

10.1530/rep.1.00360

10.1086/337944

10.1200/JCO.2003.04.094

Boland CR, 1998, A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer, Cancer Res, 58, 5248

10.1038/ng1866

Deng G, 1999, Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression, Cancer Res, 59, 2029

Gazzoli I, 2002, A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability‐high tumor, Cancer Res, 62, 3925

10.1038/sj.bjc.6600565

10.1053/j.gastro.2005.09.003

10.1056/NEJMoa064522

Kim H, 1994, Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences, Am J Pathol, 145, 148

Leach FS, 1996, Expression of the human mismatch repair gene hMSH2 in normal and neoplastic tissues, Cancer Res, 56, 235

10.1038/ng.283

10.1056/NEJMra012242

10.1093/jnci/87.15.1114

10.1016/S1542-3565(03)00314-8

10.1038/ejhg.2008.25

10.1136/gut.2005.090159

10.1002/(SICI)1097-0215(19990331)81:1<1::AID-IJC1>3.0.CO;2-K

10.1038/nrg1655

10.1038/ng1342

10.1126/science.8484122

Thibodeau SN, 1996, Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes, Cancer Res, 56, 4836

10.1111/j.1399-0004.2007.00751.x

WuY.1999. Design and application of DGGE‐based mutation detection systems for genes involved in HNPCC. Thesis University of Groningen (http://irs.ub.rug.nl/ppn/182343367).

Thông tin
Thông tin xuất bản

Genes Chromosomes and Cancer

Tập 48 Số 8

737-744

Thông tin tác giả