Background The role of mutations in proto-oncogenes and theirregulatory sequences in the pathogenesis of cancer is underclose scrutiny. Minisatellites are unstable repetitive sequencesof DNA that are present throughout the human genome. The highlypolymorphic HRAS1 minisatellite locus just downstream from theproto-oncogene H-ras-1 consists of four common progenitor allelesand several dozen rare alleles, which apparently derive frommutations of the progenitors. We previously observed an associationof the rare mutant alleles with many forms of cancer, and weundertook the present study to pursue this observation further.
Methods We conducted a case-control study, typing 736 HRAS1alleles from patients with cancer and 652 from controls by Southernblotting of leukocyte DNA. We also carried out a meta-analysisof this study and 22 other published studies, estimating therelative risk of cancer (such as bladder, breast, or colorectalcancer) when one of the rare HRAS1 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) andthe present study combined with our previous study (odds ratio,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 percent confidence interval, 1.63 to 2.30; chi-square= 57.58; P<0.001), replicated our original finding and demonstrateda significant association of rare HRAS1 alleles with cancer.We found significant associations for four types of cancer:carcinomas of the breast, colorectum, and urinary bladder andacute leukemia. We also identified suggestive but not statisticallysignificant associations for cancers of the lung and prostateand for non-Hodgkin's lymphoma.
Conclusions Mutant alleles of the HRAS1 minisatellite locusrepresent a major risk factor for common types of cancer. Althoughthe relative risk associated with the presence of one rare alleleis moderate, the aggregate prevalence of this class of mutantalleles implies an extremely important attributable risk: 1in 11 cancers of the breast, colorectum, and bladder.
Source Information
From the Division of Hematology/Oncology, Department of Medicine, Tufts University School of Medicine and New England Medical Center Hospitals, Boston (T.G.K., D.D.K., N.J.R.); and the Departments of Epidemiology and Public Health (B.D., N.R.) and Genetics (N.R.), Yale University School of Medicine, New Haven, Conn.
Address reprint requests to Dr. Krontiris at Box 245, New England Medical Center Hospitals, 750 Washington St., Boston, MA 02111.
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