4. MODIFICATION OF EXPOSURE/DISEASE RELATIONSHIPS BY GENETIC FACTORS

4.1. Family History of Breast Cancer In most epidemiological studies, the presence of breast cancer in a first-degree relative is associated with an approximate twofold elevation in breast cancer. Among women with a family history of breast cancer, a proportion of them may carry mutant alleles in BRCA1 or BRCA2, which confer a high lifetime risk of breast cancer. However, while only a small proportion of the population of women with breast cancer carry BRCA mutations (<3%), most studies indicate that approximately 15% of the cases report breast cancer in a first-degree relative. Some studies have indicated that a family history of breast cancer may alter risks associated with other factors. Sellers and colleagues reported that risks associated with hormone replacement therapy, body fat distribution, and a number of reproductive factors varied by family history of breast cancer (11-14). Other investigators have noted similar modification of risk by reported family history of a number of reproductive and dietary factors (15-22).

4.2. BRCA1 and BRCA2 Genes The identification of breast cancer susceptibility genes, BRCA1 and BRCA2, has enabled researchers to more clearly evaluate the effects of genetic predisposition on breast cancer risk, particularly among younger women (23,24). The two genes are believed to be responsible for most hereditary breast cancers, particularly early-onset breast cancer. Breast cancer associated with BRCA1 and BRCA2 has high penetrance, and predisposition is inherited as a dominant genetic trait. While this mutation is present in families with hereditary breast cancer, it was also found in 10% of a population-based cohort of women diagnosed with breast cancer before the age of 35 (25). Even for women with hereditary breast cancer, however, it appears that risk and age at onset may be modified by a number of other exogenous and endogenous factors.

There is considerable interest in the effect endogenous hormones have on risk of breast cancer among BRCA1 and BRCA2 mutation carriers. In an investigation of reproductive factors, Narod and colleagues found that low parity, but not age at first or last pregnancy, was associated with risk of developing breast cancer among women who carried the BRCA1 mutation (26). More recent evidence indicates that risk of breast cancer may be significantly reduced among BRCA1 carriers with a history of bilateral prophylactic oophorectomy (27). The proposed mechanism for this protective effect relates to the reduced exposure to endogenous ovarian hormones associated with such a procedure.

Polymorphic genes involved in endocrine processes may also influence risk of breast cancer among BRCA1 carriers. Rebbeck et al. reported that among women with a BRCA1 mutation, those with the CAG repeat-length polymorphism in the androgen receptor (AR) gene (28) and the variant AlB1 genotype (29) were at greater risk of developing breast cancer than those without these alterations. Four subsequent studies did not confirm these findings (30-33), however, Haiman et al. using data from the Nurses’ Health Study, found that longer AR repeat alleles were overrepresented among women with a family history of breast cancer (34).

There is little existing research on the effects of exogenous exposures on BRCA1/BRCA2-associated breast cancer risk. Brunet and colleagues (35) evaluated the effect of smoking on risk of breast cancer among BRCA1 or BRCA2 mutation carriers. Results from this investigation showed that smokers were at significantly reduced risk of BRCA1/BRCA2-associated breast cancer, possibly the result of the suspected antiestrogenic effect associated with cigarette smoking. Johansson et al. and Jernstrom et al. both reported that BRCA1/BRCA2 mutation status modified the effects of pregnancy-related factors on breast cancer risk (36,37).