Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

Bioinformatics and Omics Data Analytics German Cancer Research Center 69120 Heidelberg Germany

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases 69120 Heidelberg Germany

Department of Genetics and Pathology Pomeranian Medical University 71252 Szczecin Poland

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

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

Hopp Children's Cancer Center 69120 Heidelberg Germany

Institute of Bioinformatics International Technology Park Bengaluru 560066 India

Manipal Academy of Higher Education Manipal 576104 India

Medical Faculty Heidelberg Heidelberg University 69120 Heidelberg Germany

Molecular Genetic Epidemiology German Cancer Research Center 69120 Heidelberg Germany

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