AN ASSOCIATION BETWEEN THE RISK OF CANCER AND MUTATIONS IN THE HRAS1 MINISATELLITE LOCUS

Background. The role of mutations in protooncogenes and their regulato ry sequences in the pathogenesis of cancer is under close scrutiny. Mi nisatellites are unstable repetitive sequences of DNA that are present throughout the human genome. The highly polymorphic HRAS1 minisatelli te locus just downstream from the protooncogene H-ras-1 consists of fo ur common progenitor alleles and several dozen rare alleles, which app arently derive from mutations of the progenitors. We previously observ ed an association of the rare mutant alleles with many forms of cancer , and we undertook the present study to pursue this observation furthe r. Methods. We conducted a case-control study, typing 736 HRAS1 allele s from patients with cancer and 652 from controls by Southern blotting of leukocyte DNA. We also carried out a meta-analysis of this study a nd 22 other published studies, estimating the relative risk of cancer (such as bladder, breast, or colorectal cancer) when one of the rare H RAS1 alleles was present. Results. Both the present case-control study (odds ratio, 1.83; 95 percent confidence interval, 1.28 to 2.67; P = 0.002) and the present study combined with our previous study (odds ra tio, 2.07; 95 percent confidence interval, 1.47 to 2.92; P<0.001), as well as the meta-analysis of all 23 studies (odds ratio, 1.93; 95 perc ent confidence interval, 1.63 to 2.30; chi-square = 57.58; P<0.001), r eplicated our original finding and demonstrated a significant associat ion of rare HRAS1 alleles with cancer. We found significant associatio ns for four types of cancer: carcinomas of the breast, colorectum, and urinary bladder and acute leukemia. We also identified suggestive but not statistically significant associations for cancers of the lung an d prostate and for non-Hodgkin's lymphoma. Conclusions. Mutant alleles of the HRAS1 minisatellite locus represent a major risk factor for co mmon types of cancer. Although the relative risk associated with the p resence of one rare allele is moderate, the aggregate prevalence of th is class of mutant alleles implies an extremely important attributable risk: 1 in 11 cancers of the breast, colorectum, and bladder.