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.
Highlights
Lynch Syndrome (LS; or previously HNPCC – Hereditary Non-Polyposis Colorectal Cancer) is one of the most common cancer susceptibility syndromes, which accounts for approximately 1-4% of all colon cancer cases [1]
According to data from NCBI base MLH1 and MSH2 mutations account for about 90% of all mutations connected with Lynch syndrome; MHS6 accounts for 7-10% and PMS2 is found in less than 5% of these alterations
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
Summary
Lynch Syndrome (LS; or previously HNPCC – Hereditary Non-Polyposis Colorectal Cancer) is one of the most common cancer susceptibility syndromes, which accounts for approximately 1-4% of all colon cancer cases [1]. Ligtenberg et al (2009) detected similar EPCAM 3′ end deletions in four Dutch families with colorectal cancer, showing high microsatellite instability and loss of the MSH2 protein, but in which no mutations in MSH2 were found In these families the deletion co-segregated with the occurrence of MSH2-deficient tumors and, in addition, was found to lead to transcriptional read-through into the MSH2 locus [19]. Pritchard and his team from the USA (2012) notified a comprehensive and cost-effective test called “ColoSeq” that detects all classes of mutations in Lynch and polyposis syndrome genes, using solution-based targeted capture and next-generation sequencing [34] Due to this technique they correctly identified 28/28 (100%) pathogenic mutations in MLH1, MSH2, MSH6, PMS2, EPCAM, APC and MUTYH, including single nucleotide variants (SNVs), small insertions and deletions, and large copy number variants. The Coloseq assay demonstrated at least exon-level resolution for all large deletions and duplications, which was comparable or even better than the resolution of traditional approaches to these kind of mutations analysis such as MLPA, in which exact breakpoints could not be determined, because they are commonly in Alu or other repetitive DNA elements [34]
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