Thirty-two allelic restriction fragments have been detected thus far at the human Ha-ras locus. Twenty-one of these are very rare, with individual allelic frequencies less than 0.004. In a study of 800 unrelated individuals, we have demonstrated that these rare alleles occur nearly exclusively in cancer patients (P less than 0.001). From these data we have computed the relative risk for cancer associated with possession of a rare Ha-ras allele to be 23, or nearly twice the risk associated with cigarette smoking. We plan to conduct a prospective study of risk, comparing the cancer incidence in groups of cancer-patient sibs with and without rare Ha-ras alleles. At the same time we will conduct genetic studies to determined if instability of variable tandem repeat (minisatellite) loci is a significant factor in the generation of new Ha-ras alleles. Finally, we will characterize other, recently discovered deletions in the Ha-ras transcriptional control region. We hope these studies will significantly contribute to the understanding of genetic factors which govern the lifetime risk of acquiring cancer.
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