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.

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We tested over 20, 000 genes by whole-exome sequencing in 144 Polish women with breast cancer from families with strong aggregation of this tumor. We identified a new breast cancer susceptibility gene (RECQL). In Poland, there is one major founder mutations of RECQL. Our results suggest that the risk of breast cancer among the carriers is increased over 5-fold. In addition, we detected two PALB2 founder mutations in our population which predispose to poor prognosis breast cancer. Over half of breast cancer patients with a PALB2 mutation died within 10 years from the diagnosis. The survival among women with breast cancer caused by mutations of PALB2 strongly depended on tumor size. Among mutation carriers with tumors smaller than 2 cm, 10-year survival was 82%. In contrast, among mutation carriers with tumors greater than 2 cm 10-year survival was only 32%. In summary, our research enabled to identify new determinants (inherited mutations) for breast cancer, the most common malignant tumor in women. AcknowledgementsThe study was funded by the Polish National Science Centre (DEC-2011/03/ N/NZ2/01510). In diagnosis of predisposition to hereditary non-polyposis colorectal cancer (Lynch syndrome) resulting from inheritance of mutations within mismatch repair genes (MMR) it is appropriate to apply techniques in order allowing the most effective detection of these mutations. According to our experience (International Hereditary Cancer Center, PMU) which is consistent with literature data, the basic criteria for the implementation of DNA testing are pedigree and clinical data. In Poland testing based on analysis of recurrent mutations, characteristic for our population, should be performed as the first. A2 Effectiveness of detection of mutations within genes predisposing to Lynch SyndromeThen, among non-carriers of these mutations it seems to be appropriate to analyse occurrence of large rearrangements with MLPA and MMR genes expression with IHC testing. Next generation sequencing of MMR genes should be performed in cases with IHC abnormalities. The use of different protocols based upon IHC testing and sequencing in sporadic CRC results in huge increase of costs-up to a level of 150 thousand PLN for one mutation detection. The main recognized founder populations in the world are those of Finland, Sardinia, Iceland, Costa Rica, the northern Netherlands and several discrete ethic groups, including the Ashkenazi Jews. A country where there are unequivocal founder mutations is Poland where a substantial fraction of hereditary breast and prostate cancers may be explained by founder mutations in BRCA1, RECQL, PALB2, NBS1 and CHEK2 genes, respectively. For hereditary colorectal cancer (CRC), implication of Polish founder mutation has been proved only once for one of MMR (mismatch repair) genes -MLH1 (which causes Lynch syndrome (LS) when mutated). Lately, we have revealed new founder mutation in another LS-related gene -EPCAM (TACSTD1). The mechanism of pathogenesis of EPCAM caused-LS is different comparing to single germline ...