Early genetic aberrations in patients with sporadic colorectal cancer.

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high-density SNP array and exome data from The Cancer Genome Atlas (TCGA), we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon, and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm-specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (eg, APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing (WGS), we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium, and non-malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment.