Background Mutations in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Central-Eastern European counties, the founder mutations in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been precisely established in Belarus. Methods Two hundred fourteen consecutive unselected cases of ovarian cancer patients from the region of West Belarus were examined. We studied 13 founder mutations in BRCA1 (c.5266dupC, c.4035delA, c.5251C > T, c.181 T > G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C > T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7913_7917delTTCCT, c.3847_3848delGT, c.5946delT) characteristic for Central European population. Results A BRCA1 or BRCA2 founder mutations were detected in 54 of the 214 (25.2%) ovarian cancer cases. The BRCA1 c.5266dupC mutation was detected in 28 patients, followed by c.4035delA mutation observed in 18 patients. BRCA1 c.3756_3759delGTCT, c.68_69delAG, and c.1687C > T were found in 3, 2, and 1 women, respectively. BRCA2 c.658_659delGT mutation was detected in 2 ovarian cancer patients. The median age of diagnosis of the 54 hereditary ovarian cancers was 57.5 years. Conclusions The frequency of 13 causative BRCA1 and BRCA2 founder mutations in West Belarus was higher than in other Slavic countries. Testing of BRCA1 (c.5266dupC, c.4035delA, c.3756_3759delGTCT, c.68_69delAG, c.1687C > T as well as c.181 T > G) and BRCA2 (c.658_659delGT) mutations should be considered an inexpensive and sensitive test panel for this population.

In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.

LOSS OF HETEROZYGOSITY AT THE BRCA1 LOCUS AS A MARKER OF SEN- SITIVITY FOR ADJUVANT CHEMOTHERAPY IN HEREDITARY OVARIAN CANCER

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 ...

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