Increased variance in germline allele-specific expression of APC associates with colorectal cancer.

BACKGROUND & AIMS: Germline variations in allele-specific expression (ASE) are associated with highly penetrant familial cancers, but their role in common sporadic cancers is unclear. ASE of adenomatous polyposis coli (APC) is associated with pathogenesis of familial adenomatous polyposis. We investigated whether moderate variations in ASE of APC contribute to common forms of colorectal cancer (CRC).

METHODS

Denaturing high-performance liquid chromatography was used to analyze germline ASE of APC in blood samples from patients with CRC (cases, n = 53) and controls (n = 68). Means, medians, and variances of ASE were compared. Variants in the APC gene region also were analyzed.

RESULTS

The distribution of ASE differed significantly between groups; cases had significantly larger amounts of variance than controls (P = .0004). Risk for CRC increased proportionally with the degree of deviation from the mean. The odds ratio for individuals with levels of ASE that deviated more than 1 standard deviation from the mean was 3.97 (95% confidence interval, 1.71-9.24; P = .001); for those with levels greater than 1.645 standard deviations, the odds ratio was 13.46 (95% confidence interval, 1.76-609.40; P = .005). Sequence analysis revealed that a patient with a high level of ASE who did not have a family history of CRC carried a nonsense mutation in APC (p.Arg216X). Genotype analysis of APC associated multiple single-nucleotide polymorphisms with ASE values and/or variance among cases, but not controls. Cis variants, therefore, might account for some of the variance in ASE of APC.

CONCLUSIONS

Patients with CRC have a larger variance in germline levels of ASE in APC than controls; large distances from the mean ASE were associated with risk for common forms of CRC.