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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Colon Cancer Genes

Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer continued...

No interactions between the loci were associated with an increased risk of CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk of CRC. The data analyses led the authors to conclude the following:

  • The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
  • The number of common variants explaining more than 1% of inherited risk is very low.
  • Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
  • Of the common risk loci identified thus far, no significant epistatic effects were observed.

Because few of the observed associations seem to be due to correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, it seems likely that much of the common variation in cancer risk is mediated through sequence changes influencing gene expression.

A genome-wide linkage analysis was performed in 30 Swedish non-FAP/non-LS families with a strong family history of CRC.[25] Several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected by parametric and nonparametric analysis.

A GWAS of affected, unaffected, and discordant sibling pairs in 194 kindreds utilized clinical information (histopathology, size and number of polyps, and other primary cancers) in conjunction with age at onset and family history to define five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancers) prior to analysis.[26] 1p31.1 strongly linked to the multiple-cancer subgroup (P < .00007). 15q14-q22 linked to the full-sample (P < .018), oligopolyposis (P < .003), and young (P < .0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome in families of Ashkenazi descent. BRCA2 linked with the colon/breast phenotypic subgroup. Linkage to 17p13.3 in the breast/colon subgroup identified HIC1 (hypermethylated in colon cancer 1) as a candidate gene.

Nonparametric analysis revealed three loci at 3q29 (logarithm of the odds [LOD] score = 2.61; P = .0003), 4q31.3 (LOD = 2.13; P = .0009), and 7q31.31 (LOD = 3.08; P = .00008) in a GWAS performed in 70 kindreds with at least two siblings affected with colorectal adenocarcinoma or colorectal polyps with high-grade dysplasia.[27] Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.

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