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Association Between the T29C Polymorphism in the Transforming Growth Factor 1 Gene and Breast Cancer Among Elderly White Women

The Study of Osteoporotic Fractures

Elad Ziv, MD; Jane Cauley, DrPH; Phillip A. Morin, PhD; Robert Saiz, BS; Warren S. Browner, MD,MPH

JAMA. 2001;285:2859-2863.

Context  Transgenic animal experiments suggest that increased expression of transforming growth factor 1 (TGF-1) is protective against early tumor development, particularly in breast cancer. A TC (thymine to cytosine) transition in the 29th nucleotide in the coding sequence results in a leucine to proline substitution at the 10th amino acid and is associated with increased serum levels of TGF-1.

Objective  To determine whether an association exists between this TGF-1 polymorphism and breast cancer risk.

Design, Setting, and Participants  The Study of Osteoporotic Fractures, a prospective cohort study of white, community-dwelling women aged 65 years or older who were recruited at 4 US centers between 1986 and 1988. Three thousand seventy-five women who provided sufficient clinical information, buffy coat samples, and adequate consent for genotyping are included in this analysis.

Main Outcome Measure  Breast cancer cases during a mean (SD) follow-up of 9.3 (1.9) years, verified by medical chart review and compared by genotype.

Results  Risk of breast cancer was similar in the 1124 women with the T/T genotype (56 cases; 5.4 per 1000 person-years) and the 1493 women with the T/C genotype (80 cases; 5.8 per 1000 person-years) but was significantly lower (P = .01) in the 458 women with the C/C genotype (10 cases; 2.3 per 1000 person-years). In analyses that adjusted for age, age at menarche, age at menopause, estrogen use, parity, body mass index, and bone mineral density, women with the C/C genotype had a significantly lower risk of developing breast cancer compared with women with the T/T or T/C genotype (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.17-0.75). There was no significant difference between the risk for women with the T/C genotype compared with women with the T/T genotype (adjusted HR, 1.04; 95% CI, 0.73-1.48).

Conclusions  Our findings suggest that TGF-1 genotype is associated with risk of breast cancer in white women aged 65 years or older. Because the T allele is the common variant and confers an increased risk, it may be associated with a large proportion of breast cancer cases.

Author Affiliations: Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center (Drs Browner and Ziv), Departments of Medicine (Drs Browner and Ziv) and Epidemiology and Biostatistics (Dr Browner), University of California, San Francisco; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa (Dr Cauley); and Axys Pharmaceutical Inc, La Jolla, Calif (Dr Morin and Mr Saiz). Dr Browner is now with the California Pacific Medical Center Research Institute, San Francisco; Dr Morin is now with the Max Plank Institute for Evolutionary Anthropology, Leipzig, Germany; and Mr Saiz is now with Althea Technologies, San Diego, Calif.

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