An intronic germline transition in the HNPCC gene hMSH2 is associated with sporadic colorectal cancer.

The aim of this study was to determine whether an intronic germline substitution in the hereditary non-polyposis colorectal cancer (HNPCC) gene hMSH2 represents a genetic risk factor for sporadic CRC. Possible effects of this substitution were investigated by assessment of microsatellite instability and hMSH2 cDNA sequencing. Constitutional DNA from patients with sporadic CRC and healthy controls from the same region in Germany was analysed for the intronic germline T-->C transition six bases upstream of exon 13 of hMSH2. 29 of 106 patients (27%) were found to harbour the germline T-->C transition as opposed to only 13 of 125 controls (10%; P < 0.001; OR 3.2, CI 1.58-6.63). CRCs from patients with the substitution displayed neither clinical HNPCC-like features nor an increased rate of microsatellite instability. No abnormal cDNA sequence was found at the exon 12-13 border. These data suggest a 3.2-fold increased risk of sporadic CRC for individuals with the intronic hMSH2 transition. However, this substitution might not be pathogenic itself, but may be linked to a locus nearby that is.