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The BRCA2 372 HH Genotype Is Associated with Risk of Breast Cancer in Australian Women Under Age 60 Years¹

Oncology Division, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research and The University of Queensland, Brisbane, 4029 Australia [A. B. S., X. C., G. C-T.]; Centre for Genetic Epidemiology, The University of Melbourne, Carlton, 3053 Australia [J. L. H., G. S. D., J. C.]; The New South Wales Cancer Council, Kings Cross, 2011 Australia [M. R. E. M.]; Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand [M. R. E. M.]; The Anti-Cancer Council of Victoria, Carlton, 3053 Australia [G. G. G.]; Peter MacCallum Cancer Institute, Melbourne, Australia and Department of Pathology, The University of Melbourne, Parkville, 3052 Australia [S. E-S., D. J. V., M. C. S.]; and School of Public Health, Queensland University of Technology, Kelvin Grove, 4059 Brisbane, Australia [B. N.]

The BRCA2 N372H nonconservative amino acid substitution polymorphism appears to affect fetal survival in a sex-dependent manner, and the HH genotype was found to be associated with a 1.3-fold risk of breast cancer from pooling five case-control studies of Northern European women. We investigated whether the BRCA2 N372H polymorphism was associated with breast cancer in Australian women using a population-based case-control design. The BRCA2 372 genotype was determined in 1397 cases under the age of 60 years at diagnosis of a first primary breast cancer and in 775 population-sampled controls frequency matched for age. Case-control analyses and comparisons of genotype distributions were conducted using logistic regression. All of the statistical tests were two-tailed. The HH genotype was independent of age and family history of breast cancer within cases and controls, and was more common in cases (9.2% versus 6.5%). It was associated with an increased risk of breast cancer, 1.47-fold unadjusted (95% confidence interval, 1.05–2.07; P = 0.02), and 1.42-fold (95% confidence interval, 1.00–2.02; P = 0.05) after adjusting for measured risk factors. This effect was still evident after excluding women with any non-Caucasian ancestry or the 33 cases known to have inherited a mutation in BRCA1 or BRCA2, and would explain 3% of breast cancer. The BRCA2 N372H polymorphism appears to be associated with a modest recessively inherited risk of breast cancer in Australian women. This result is consistent with the findings for Northern European women.

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