SO10: Identification of genetic biomarkers for clinical management of familial colorectal cancer

Mev Dominguez-Valentin1, Sigve Nakken1, Daniel Vodak1, Pål Møller1,4,5, Eivind Hovig 1,2,3

1 – Department of Tumour Biology, Institute for Cancer Research. 2 – Institute of Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway. 3 – Institute of Informatics, University of Oslo, Norway. 4 – Department of Medical Genetics, Oslo University Hospital, Norway. 5 – Department of Human Medicine, Universität Witten/Herdecke, Germany.


To identify inherited genetic factors that influence biological and clinical characteristics of CRC developed in high-risk patients.


The hereditary cancer registry from the Norwegian Radium Hospital was used to identify non-related high-risk CRC individuals (n=51) where no disease-predisposing mutations in MLH1, MSH2, MSH6 and PMS2 genes had been found by Sanger DNA sequencing. Forty-four cancer genes reported to carry risk of familial breast or CRC were selected and analyzed by an amplicon-based assay for targeted resequencing (TSCA, Illumina, Palo Alto, CA).


We identified 2 variants with a predicted deleterious mutation in CHEK2 (i.e. p.I157T and c.319+2T>A), and 7 variants of uncertain significance including variants in CHEK2, MLH1, MSH2, MUTYH and NOTCH3. The minor allele frequencies (MAF) in these variants were very low or no frequency data have been reported. Pathogenicity prediction algorithms were applied and suggest that 6/7 (87%) of these variants were probably pathogenic and should be further studied with segregation analyses and in vitro testing. In sum 8/51 (16%) of the patients tested had pathogenic or probably pathogenic variants described.


Our study provides new information on variants on genetic loci that may affect the risk of developing cancer in these patients and their families.