Investigation of genetic factors involved in colorectal cancer predisposition

Abstract: Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the western world. Several hereditary CRC predisposing syndromes have been described and their genetic component has been elucidated. Taken together, these syndromes account for at most 5% of all CRC cases. Twin studies have, however, suggested a much stronger contribution of genetic factors suggesting that a number of CRC predisposing genes remain to be identified. The genome-wide linkage analysis in 18 non-FAP/non-HNPCC colorectal cancer families revealed regions of interest on three chromosomes, when the analysis was performed under the assumption of locus heterogeneity. The region on chromosome 22q was suggested in the parametric analysis, while the results of both parametric and nonparametric analysis provided support for the regions on chromosomes 11q and 14q. After finemapping of the regions on chromosomes 11q and 14q both the HLOD score and the NPL scores were reduced but still within the range of suggestive linkage. Families exhibiting linkage to chromosomes 11 and 14 were identified and overlapping regions were determined (1 1q13.2-13.4, 1 1q22.1- 23.1 and 14q23.1-24.1). (Paper I) The SMARCA3 gene has been shown to be a common target for methylation in colon and gastric cancer. Germline mutation screening of the SMARCA3 gene was performed in order to evaluate the role of this gene among Swedish colorectal cancer patients, some of whom also had a family history of gastric cancer. The lack of pathogenic germline mutations suggests that the gene has very little role, if any, in the predisposition to colorectal and gastric cancer. Several identified variants in the SMARCA3 gene could act as modifying or low-risk alleles, however additional studies are needed to determine their role. (Paper II) The CHEK2 1100delC, novel low-risk breast cancer predisposing allele, has been found at particularly high frequency in families with both colorectal and breast cancer. To investigate the possible role of this variant in CRC predisposition the variant frequency was determined in CRC cases and controls. No over-representation of the variant was detected in cases. However, due to the low frequency of the variant in the Swedish population, a very low penetrance effect of CHEK2 1100delC could not be excluded. (Paper III) Bi-allelic germline mutations in the MUTYH gene are known to predispose to recessively inherited MAP syndrome, characterized by the occurrence of an increased number of colonic polyps. We found no evidence for the contribution of MUTYH in familial CRC with a low polyp number. The two most common MUTYH mutations, Y165C and G382D, have been identified in the Swedish population and evidence for a slightly increased CRC risk among heterozygote carriers of these mutations was seen. In addition, three novel variants affecting the same amino acid position, R423Q, R423P and R423R, have been detected among sporadic CRC cases, however their significance remains to be determined. (Paper IV)