Germline hypermethylation of MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. Genes Chromosomes Cancer

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Genes Chromosomes and Cancer (Impact Factor: 4.04). 08/2009; 48(8):737-44. DOI: 10.1002/gcc.20678
Source: PubMed


It 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.

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    • "Introduction Lynch syndrome (LS) is an autosomal dominantly inherited condition caused by a germline mutation in one of four DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. Loss of expression of MSH2 is also associated with mutations in EPCAM [1] [2] [3] [4] [5]. Lynch syndrome is part of hereditary nonpolyposis colorectal cancer (HNPCC), where affected families are defined by family history criteria known as the Amsterdam criteria. "
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    ABSTRACT: Objective: The primary aim of this study was to determine the prevalence of occult gynecologic malignancy at the time of risk reducing surgery in patients with Lynch Syndrome. A secondary aim was to determine the prevalence of occult gynecologic malignancy at the time of surgery for non-prophylactic indications in patients with Lynch Syndrome. Methods: A retrospective review of an Inherited Colorectal Cancer Registry found 76 patients with Lynch syndrome (defined by a germline mutation in a DNA mismatch repair gene) or hereditary nonpolyposis colorectal cancer (HNPCC) (defined by Amsterdam criteria) who had undergone hysterectomy and/or salpingo-oophorectomy for a prophylactic or non-prophylactic indication. Indications for surgery and the prevalence of cancer at the time of each operation were reviewed. Results: 24 of 76 patients underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy for Lynch syndrome or HNPCC. In 9 of these patients, a benign indication for surgery was also noted. 4 of 24 patients (17%, 95% CI = 5-38%) were noted to have cancer on final pathology. 20 of 76 patients (26%) undergoing operative management for any indication were noted to have occult malignancy on final pathology. Conclusions: Patients should be counseled about the risks of finding gynecologic cancer at the time of prophylactic or non-prophylactic surgery for Lynch syndrome and HNPCC, and the potential need for additional surgery.
    Full-text · Article · Nov 2013 · Gynecologic Oncology
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    • "Recently, it was demonstrated that germline 3' end deletions of the EPCAM gene lead to Lynch syndrome through hypermethylation of the MSH2 promoter region (Ligtenberg et al., 2009) (see Figure 1e). To date several distinct EPCAM terminal deletions have been detected worldwide and it is estimated that approximately 19–27% of cases leading to loss of MSH2 expression without germline MSH2 mutation are associated with transcription-mediated inactivation via epigenetic regulation (Kovacs et al., 2009; Niessen et al., 2009). Later, the same group showed that the tumour suppressor gene PTPRJ can be epigenetically silenced through a similar mechanism as occurs in early onset CRC patients (Venkatachalam et al., 2010). "

    Full-text · Article · Sep 2013
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    • "Based on previous worldwide results, there is a strong suggestion that implementation of EPCAM deletion mapping in routine diagnostics on suspected Lynch syndrome families should be considered. Some studies suggest that the frequency of EPCAM deletions as a cause of Lynch syndrome is up to 30% in patients with MSH2–negative tumors (from IHC results) or approximately 20% of LS patients without a mutation in MMR genes [18,22]. "
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    ABSTRACT: Lynch syndrome (clinically referred to as HNPCC -- Hereditary Non-Polyposis Colorectal Cancer) is a frequent, autosomal, dominantly-inherited cancer predisposition syndrome caused by various germline alterations that affect DNA mismatch repair genes, mainly MLH1 and MSH2. Patients inheriting this predisposition are susceptible to colorectal, endometrial and other extracolonic tumors. It has recently been shown that germline deletions of the last few exons of the EPCAM gene are involved in the etiology of Lynch syndrome. Such constitutional mutations lead to subsequent epigenetic silencing of a neighbouring gene, here, MSH2, causing Lynch syndrome. Thus, deletions of the last few exons of EPCAM constitute a distinct class of mutations associated with HNPCC. Worldwide, several investigators have reported families with EPCAM 3'end deletions. The risk of colorectal cancer in carriers of EPCAM deletions is comparable to situations when patients are MSH2 mutation carriers, and is associated with high expression levels of EPCAM in colorectal cancer stem cells. A lower risk of endometrial cancer was also reported. Until now the standard diagnostic tests for Lynch syndrome have contained analyses such as immunohistochemistry and tests for microsatellite instability of mismatch repair genes. The identification of EPCAM deletions or larger EPCAM-MSH2 deletions should be included in routine mutation screening, as this has implications for cancer predisposition.
    Full-text · Article · Aug 2013 · Hereditary Cancer in Clinical Practice
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