Roger Milne and Georgia Chenevix-Trench
Queensland Institute of Medical Research, Brisbane, Queensland, Australia
The incomplete penetrance associated with mutations in BRCA1 and BRCA2 suggests that environmental or genetic risk-modifying factors may exist that affect the phenotype of BRCA1 and BRCA2 mutation carriers. Initial estimates from clinic-based data indicated that around 80% of carriers of mutations in BRCA1 and BRCA2 from multiple-case families would develop breast cancer (1,2), whereas a later pooled analysis from population-based studies has suggested that for the great majority of mutation carriers, their average lifetime risk is closer to 45% to 66% (3). This pooled-analysis of BRCA1 and BRCA2 carriers also showed that in BRCA1 mutation carriers, the breast cancer penetrance for relatives ascertained through a breast cancer case was significantly higher than for those ascertained through an ovarian cancer case, and even higher if the index case was diagnosed before the age of 35 (3). Conversely, the ovarian cancer risk was higher in families ascertained through an ovarian cancer index case. Similar differences in risk, depending on the cancer site in the index case, were also reported by Simchoni et al. in an Ashkenazi Jewish population (4). These variations in risk between different studies, and according to the phenotype of the proband, are consistent with the presence of modifying factors. There is also a recent report that the phenocopy rate in BRCA1 and BRCA2 families is increased over the population rate, further suggesting the existence of environmental or genetic modifiers (5).
Environmental or lifestyle factors may be important in explaining the variation in breast cancer risk among BRCA1 and BRCA2 mutation carriers. Estimates of risk in carriers may vary between countries for cultural reasons. For example, parity (number of full-term pregnancies), oral contraceptive use, and oophorectomy all influence the risks of breast cancer, and these factors vary between countries (6). That the risk of breast cancer for BRCA1 and BRCA2 mutation carriers appears to have increased over calendar time (7-9) strengthens the argument for the existence of environmental determinants of risk in the carrier population (10).
Options to reduce of breast cancer risk which are available to unaffected carriers of mutations in BRCA1 and BRCA2 are discussed elsewhere in this volume. Briefly, they include chemoprevention, and surveillance [by regular self-examination of the breasts, clinical breast examination, mammography, ultrasound and/or magnetic resonance imaging (MRI)] as well as prophylactic bilateral mastectomy and prophylactic bilateral oophorectomy (105). Apart from prophylactic mastectomy and oophorectomy, there is little consistent information about what BRCA1 and BRCA2 carriers can do to reduce their risk. If modifiable environmental or lifestyle factors were identified that affected breast cancer risk in carriers, a perhaps more acceptable alternative would be to inform these women of how they can change their habits or lifestyle to reduce their risk. It cannot necessarily be assumed that the widely recognized risk factors for breast cancer in the general population, such as reproductive and hormonal factors, operate in the same way in women who carry mutations in BRCA1 and BRCA2. While there have been number of relatively recent publications addressing this issue by studying mutation carriers, a variety of methodological challenges complicate our ability to draw strong inferences from these studies. Thus, few firm conclusions have been drawn about the role of modifiers to date.
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