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Genetic Polymorphisms and Colorectal Cancer Risk

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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.[14] 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 cancer) prior to analysis.[15] 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 (HMPS) 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.[16] Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.

Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association Studies

ChromosomeLogarithm of the Odds (LOD) Score/Odds Ratio (OR)P ValueSingle Nucleotide Polymorphism (SNP)Marker
ORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes.
a Identified in a breast/colon cohort.
3q29LOD = 2.61[16].0003 D3S240
4q31.3LOD = 2.13[16].0009 D4S2999
7q31.31LOD = 3.08[16].00008 D7S643
8q23.3Combined OR = 1.29[13]1.1 × 10-10rs11986063 
8q23.3ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43[11]3.3 × 10-18rs16892766 
Combined OR = 1.32[13]1.1 × 10-10
8q24ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57[11]7.0 × 10-11rs6983267 
Combined OR = 0.83[13]2.1 × 10-14
8q24OR = 1.19[12]8.6 × 10-26rs7014346 
Combined OR = 1.21[13]3.0 × 10-13
8q24Combined OR = 1.17[13]1.2 × 10-10rs7837328 
8q24Combined OR = 1.14[13]1.5 × 10-7rs10808555 
10p14ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80[11]2.5 × 10-13rs10795668 
Combined OR = 0.91[13]3.1 × 10-4
11q23OR = 1.11[12]5.8 × 10-10rs3802842 
Combined OR = 1.21[13]5.2 × 10-13
14q22.2Combined OR = 1.11[13]8.1 × 10-10rs4444235 
15q13ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70[11]4.7 × 10-7rs4779584 
Combined OR = 1.19[13]1.7 × 10-8
16q22.1Combined OR = 0.91[13]1.2 × 10-8rs9929218 
17p13.3aNot available[15].0364 D17S1308
18q21ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73[11]1.7 × 10-6rs4939827 
OR = 1.20[12]7.8 × 10-28
Combined OR = 0.85[13]2.2 × 10-11
19q13.1Combined OR = 0.89[13]2.2 × 10-7rs7259371 
19q13.1Combined OR = 0.87[13]4.6 × 10-9rs10411210 
20p12.3Combined OR = 1.12[13]2.0 × 10-10rs355527 
20p12.3Combined OR = 1.12[13]2.1 10-10rs961253 
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