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.

Bioinformatics and Omics Data Analytics German Cancer Research Center Heidelberg Germany

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases Heidelberg Germany

Department of Genetics and Pathology Pomeranian Medical University in Szczecin Szczecin Poland

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Institute of Bioinformatics International Technology Park Bangalore India

Manipal Academy of Higher Education Manipal Karnataka 576104 India

Medical Faculty Heidelberg Heidelberg University Heidelberg Germany

Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

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