DNA damage response pathway mutations contribute to a high proportion of hereditary colorectal cancer in patients from the Republic of Macedonia.

512Background: Hereditary factors are assumed to play а role in 35-45% of all colorectal cancers with 5%-10% associated with high penetrant disease-causing mutations in genes correlating to hereditary polyposis (HP) or hereditary nonpolyposis syndromes (HNPCC). Although inherited germline mismatch repair and APC gene mutations contribute significantly to CRC, still a genetic diagnosis cannot be obtained in > 50% of familial cases. Methods: We performed a targeted NGS sequencing of 103 probands with clinically diagnosed HP (39) or HNPCC (64) using a multigene panel on two different platforms (Illumina Cancer Panel and Ion Torrent custom panel) covering coding and exon/intron sequences of 100 genes implicated in hereditary cancers. Results: Overall, the molecular defect was identified in 60 (58%) index patients. As expected, a large percentage (82%) of these patients exhibited the presence of clearly pathogenic mutations in well-known genes associated with hCRC (APC, MUTYH, BMPR1A, NTHL1 in HP, MLH1, MSH2, ...