BACKGROUND: Family history of colorectal cancer (CRC) and multiple primary CRCs in a single person may indicate inherited CRC predisposition. METHODS: In the present study, we performed whole exome/genome sequencing on germline DNA from at least two CRC cases in 19 families and from family members with a double primary CRC from seven additional families. We used a set of in silico predictions in combination with a STRING protein-protein interaction and pathway analysis to identify the most likely variants predisposing to CRC. RESULTS: We identified Cell cycle/DNA repair and TGFβ signaling/Focal adhesion/Extracellular matrix organization pathways as highly significant protein-protein interaction networks. Variants in the APCDD1, CYBA, PTK7 and SRC genes were identified in more than one family, and they were shown to dysregulate basic cellular functions, potentially leading to cancer development. Most variants were private to a family, and each family had more than one candidate variant, suggesting a synergistic or polygenic mode of inheritance. This hypothesis, as well as validation of the identified variants and pathways and their functional consequences, need confirmation by other family-based studies. CONCLUSIONS: Different types of family-based analyses together with in silico predictions are helpful to identify candidate genes and pathways for CRC predisposition.

Biomedical Center Faculty of Medicine Charles University Pilsen Alej Svobody 1665 76 32300 Pilsen Czech Republic

Chair of Drug and Cosmetics Biotechnology Warsaw University of Technology Warsaw Poland

Clinical Cooperation Unit Molecular Hematology Oncology German Cancer Research Center Heidelberg Germany

Department of Genetics and Pathology International Hereditary Cancer Center Pomeranian Medical University in Szczecin Szczecin Poland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Immune Regulation in Cancer German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Im Neuenheimer Feld 580 69120 Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

State Key Laboratory of Oncogenes and Related Genes Shanghai Cancer Institute Renji Hospital Shanghai Jiao Tong University School of Medicine Shanghai China

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