Loss of heterozygosity at the ATM locus in colorectal carcinoma

Patients homozygous for mutation of the ATM gene exhibit constitutional gen etic instability and have a high risk of cancer. A-T heterozygotes also hav e an increased tendency to develop adenocarcinomas. Colorectal cancer (CRC) is the second most common cancer in western populations, and tumors of the right colon are typically highly genetically unstable. The DNA mismatch re pair genes mutated in most familial and some sporadic CRCs account for one route by which cells acquire additional oncogenic mutations during the prog ression of malignancy. Mismatch repair defects, however, do not seem to acc ount for the majority of CRCs. Because of its role in maintaining genomic s tability, and the high risk of cancer to homozygotes, ATM is a candidate ge ne for inactivation in the evolution of chromosomal instability in tumor ce lls. We have examined 114 CRC patients for loss of heterozygosity (LOH) usi ng six microsatellite markers tightly linked to the ATM locus. Our data sug gest that LOH of this region is not associated with cancer of the proximal colon. In the distal colon, LOH was found in 23-31% of cases, which is mode rately elevated above the non-specific LOH reported in tumors of this tissu e. No correlations were found with regard to clinicopathological variables aside from tumor location.