Genetic studies of colorectal cancer

Abstract

Colorectal cancer is the third most commonly diagnosed cancer worldwide with an incidence rate of over 1 million cases per year. A genetic contribution has been suggested to be involved in around 35% of all colorectal cancer cases. However, mutations in single high-penetrance genes have been identified in only approximately 5% of all cases, leaving the majority of the genetic burden unexplained. Some of this might be attributable to additional high-penetrance genes, however, it is of general belief that low- to moderate penetrance alleles are responsible for a large proportion of the remaining genetic predisposition for colorectal cancer.

In an attempt to identify novel colorectal cancer predisposing loci, genome-wide linkage analysis was performed in 18 non-FAP/non-HNPCC colorectal cancer families. No common susceptibility locus was identified thus providing evidence for locus heterogeneity. Analysis assuming locus heterogeneity revealed three regions of interest; one region on chromosome 22q12 was suggested from parametric linkage analysis and two regions on chromosomes 11q and 14q from both parametric and non-parametric linkage analyses. Finemapping of chromosomes 11q and 14q reduced the LOD scores, but remained suggestive for linkage. Haplotype analysis in families with disease linked to chromosomes 11 and 14 gave the following overlapping regions; 11q13.2-13.4, 11q22.1-23.1, and 14q23.1-24.1.

A novel susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.2-31.2 has been suggested from sib-pair studies. Analysis of an extended Swedish colorectal cancer family, which had in a previous genome screen shown suggestive linkage to this region, gave evidence of linkage of adenoma and colorectal cancer to chromosome 9q22.32-31.1 with a multipoint LOD score of 2.4. Haplotype analysis defined the region to 7.9 cM between the markers D9S280 and D9S277. Hence, these data supports the evidence of a susceptibility locus predisposing to adenoma and colorectal cancer at this chromosomal region.

Genotyping additional 19 non-FAP/non-HNPCC colorectal cancer families for this region revealed suggestive linkage of disease in seven other families. In an attempt to identify the disease causing gene, the coding regions of totally 9 putative candidate genes were screened for germline mutations. TGFBR1 was also investigated for genomic deletions, insertions and rearrangements with no aberrations or structural variations detected.

A common variant, TGFBR1*6A, of the TGFBR1 gene has been reported to be associated with an increased risk for colorectal cancer. Most recently, this variant has been proposed to be directly causally responsible for a proportion of familial colorectal cancer. A second polymorphic variant of TGFBR1, Int7G24A, has also been implicated in cancer susceptibility. Using a case-control design, TGFBR1*6A and Int7G24A allele frequencies in 83 HNPCC and 179 non-HNPCC familial colorectal cancer cases were compared with 856 population-based controls. While the frequency of the TGFBR1*6A allele was similar in non-HNPCC familial cases and controls, the frequency in HNPCC cases was elevated compared to the controls. No association was found between the Int7G24A variant and colorectal cancer risk.

To further clarify the role of the TGFBR1*6A variant in colorectal cancer predisposition, a case-control study of 1,042 unselected colorectal cancer cases and 856 population controls was performed . The frequency of TGFBR1*6A was not significantly different between cases and controls. A subsequent meta-analysis of all published case-control studies on the TGFBR1*6A variant and colorectal cancer risk gave an odds ratio of 1.13 (95% CI: 0.98-1.30) for TGFBR1*6A carriers. In conclusion, these data provide little evidence to support the hypothesis that TGFBR1*6A acts as a colorectal cancer susceptibility allele.