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

About 15% of colorectal cancer (CRC) patients have first-degree relatives affected by the same malignancy. However, for most families the cause of familial aggregation of CRC is unknown. To identify novel high-to-moderate-penetrance germline variants underlying CRC susceptibility, we performed whole exome sequencing (WES) on four CRC cases and two unaffected members of a Polish family without any mutation in known CRC predisposition genes. After WES, we used our in-house developed Familial Cancer Variant Prioritization Pipeline and identified two novel variants in the solute carrier family 15 member 4 (SLC15A4) gene. The heterozygous missense variant, p. Y444C, was predicted to affect the phylogenetically conserved PTR2/POT domain and to have a deleterious effect on the function of the encoded peptide/histidine transporter. The other variant was located in the upstream region of the same gene (GRCh37.p13, 12_129308531_C_T; 43 bp upstream of transcription start site, ENST00000266771.5) and it was annotated to affect the promoter region of SLC15A4 as well as binding sites of 17 different transcription factors. Our findings of two distinct variants in the same gene may indicate a synergistic up-regulation of SLC15A4 as the underlying genetic cause and implicate this gene for the first time in genetic inheritance of familial CRC.

• Klíčová slova
• Familial colorectal cancer, Germline variant, SLC15A4, Whole exome sequencing,
• MeSH
• genetická predispozice k nemoci MeSH
• kolorektální nádory * genetika   patologie   MeSH
• lidé MeSH
• membránové transportní proteiny genetika   MeSH
• proteiny nervové tkáně genetika   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• zárodečné buňky patologie   MeSH
• zárodečné mutace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• membránové transportní proteiny MeSH
• proteiny nervové tkáně MeSH
• SLC15A4 protein, human MeSH Prohlížeč