A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.

• Klíčová slova
• familial colorectal cancer, germline variant, multiple primaries, whole‐exome sequencing,
• MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• oprava DNA genetika   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• senioři MeSH
• zárodečné mutace * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH