Low-Penetrance Genotypes and Gene-Environment Interactions

A region linked to the HRAS1 protooncogene, consisting of 30 to 100 copies of a 28 base-pair repeat, has been studied with respect to risk of a wide variety of cancers. Several alleles (repeat lengths) are common, and a large number of rare alleles of varying length are found. Among women with at least one rare allele, risk of breast and a number of other cancers was approximately doubled. In a case control study with 160 cases, a similar elevation in risk was seen, and a stronger association was observed among African-Americans than among white women. The functional significance of these rare alleles is uncertain.

Ataxia-Telangiectasia Gene
Analyses of pedigrees from families in which autosomal recessive transmission of ataxia-telangiectasia had been demonstrated suggested that women who were heterozygous for the ataxia-telangiectasia gene (ATM) were at approximately fivefold increased risk of breast cancer. The gene has been cloned, but it is very large and detection of mutations is difficult. In an analysis that detected mutations causing protein truncation, these mutations were detected in 2 of 401 women with early-onset breast cancer and 2 of 202 controls; these results suggest that heterozygosity for the ATM gene is unlikely to be an important cause of breast cancer at young age.

Summary of Low-Penetrance Genotypes and Breast Cancer Risk
No low-penetrance genes may be confidently associated with breast cancer risk. This is perhaps not surprising, as only a limited number of candidate genes have been examined, and for most of these only one or two polymorphisms have been tested. Other relevant candidate genes remain to be studied, and undoubtedly many candidates have yet to be discovered and cloned. The difficulty of assessing the functional significance of polymorphisms remains a barrier to selection of the most promising polymorphisms to examine. To assess gene-environment interactions, large studies with high-quality data on the environmental exposures are required; few such studies exist.

Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz

W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
B. Rockhill: Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts
D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts
G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts


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