Using the affected sibling-pair approach to identify genetic regions involved in common familial colorectal, a major locus has been identified on chromosome 7q31. This region clearly stands out from the rest of the genome demonstrating linkage at multiple genetic markers over a 13.6 cM region when either study allele frequencies or CEPH allele frequencies are used in the analysis. A region on chromosome 7 with linkage (NPL LOD 1.85, p=0.032) is also reported by Kemp et al. when analysis was restricted to 38 families with colorectal cancer as the diagnosis 8
. The reported peak spans approximately 80 to 110 Mbp, whereas our peak spans 107 to 129 Mbp on chromosome 7.
Interestingly, LOH of one or more markers in the 7q31.1-31.2 around marker D7S522 region has been reported in a series of 11 of 18 colon carcinoma cases, with the maximum LOH at D7S522 (115.9 Mbp), within the region identified in this study. The authors suggest that a tumor suppressor gene relevant to the development of epithelial cancers is present in this region 24
. Certainly, the MET gene is in this region of LOH at 116.1 Mbp.
Additionally, the ERBB4 gene is near a peak identified through the recessive parametric model on 2q33.3. A functional polymorphism at -782G>T in this gene was recently reported as a risk factor in colorectal cancer (OR 2.21, 95% CI 1,22-3.99) and will be important to examine in this sibling pair population 19
The study was originally designed to be much larger based on modeling and power estimates to detect linkage as described by Kerber et al., 2008 25
(manuscript in press). Considering the minimum observed p-value of 0.0001 as a critical threshold, and taking the relatively conservative value of 0.2 as an estimated attributable risk for inherited susceptibility to colon cancer, we see reasonable (≥ 10%) power only if this locus accounts for the majority of the heritable effect, either because of high penetrance or high prevalence. It is not clear that the majority of heritable CRCs can be explained by variation at this locus, so we might wish to consider alternative explanations. Two details of the modeling may have resulted in over-conservative power estimates when compared to the study as we have actually carried it out: 1) the markers employed are far more heterogeneous than the 4-allele markers simulated; and 2) the multipoint methods employed in the present study using intervals of 1 cM may have considerably more power than the simulated tests. These two factors probably interact to increase power, so estimates may be quite conservative. Nevertheless, the p-values we have observed are surprisingly small considering the study design and sample size.
Although this is one of the largest colorectal cancer sibling-pair studies reported thus far, a major limitation is nonetheless its size, 75 families with DNA from two or more affected individuals. A strength as well as a challenge of our study was to restrict enrollment to individuals with invasive colorectal cancer or an adenoma with high grade dysplasia or carcinoma in-situ. This was a challenge due to the high mortality of colorectal cancer; it was difficult to enroll two siblings surviving colorectal cancer and willing to participate in research. Other groups have done similar studies, but included fewer families and less penetrant phenotypes, such as the presence of advanced adenomas (≥1cm) 7
or any colonic polyp including benign hyperplastic polyps 8
. As Kemp et al. report, distinct genetic loci are identified when the study set is restricted to colorectal cancer.
Use of the CEPH allele frequencies for linkage analysis consistently results in higher LOD scores (vs. the study allele frequencies). This is most likely due to minor alleles being over represented in the CEPH data set. Since the CEPH allele set is limited to 13 individuals and 5% the size of the study allele set, this is not surprising. The one peak on chromosome 3, using only CEPH allele frequencies, is interesting in that it is close to MLH1 and might represent a marker commonly found in the study population and linked to a pathogenic MLH1 variant.
Further confirmatory studies as well as expansion of the study population size are needed to confirm this 7q31 locus and identify other genetic loci contributing to hereditary colorectal cancer risk in the population. Investigation of genes within this region will be equally important, especially regulatory or coding SNPs that may be enriched in the colorectal cancer population. Finally, evaluation of LOH in tumor blocks in regions showing linkage, especially the 7q31 region which has demonstrated LOH in sporadic colorectal cancers, would provide further evidence for region containing a tumor suppressor gene responsible for familial colorectal cancer.