Abstract
Breast cancer, like many common diseases, has a substantial component of heritable risk. Very high risk genes are rare and the most common, highly penetrant, dominantly inherited breast cancer predisposition genes are BRCA1 and BRCA2. Not only do these genes confer a high lifetime risk of developing breast cancer but also a substantial increase in the risk of developing ovarian cancer.
These genes usually create a striking pattern of disease within families and can be easy to ‘spot’ but sometimes the pattern is not so striking for various reasons including the family structure and reduced penetrance of the disease gene. The management of a known high-risk gene carrier includes bilateral salpingo-oophorectomy often before the time of the natural menopause thus inducing an early surgical menopause. Without ignoring the potential adverse symptoms created by a premature menopause, it is important to note that a premature menopause does reduce the long-term breast cancer risk (an effect also seen in the general population but amplified in gene carriers because of the much higher a priori breast cancer risk. There are risks and benefits in this group that need to be considered and discussed and can guide a patient's choice about the use of hormone replacement therapy (HRT).
The broader picture of breast cancer genetic susceptibility is however more complex. In a much larger proportion of the population than these rare genetic mutations account for, genetic susceptibility exists and can be inferred in many families with a history of breast cancer. This type of familial clustering of disease is now thought to be largely due to genetic variants (mutations) that are rather frequent in the population (at least 5% or more will carry the susceptibility gene), but these have only a low penetrance causing individual risks of 1.2–2 times of the average population risk. This is in contrast to the rare genetic variants (mutations) like BRCA1 or BRCA2 where the increase in risk of acquiring breast cancer by the age of 50, e.g. is 30–40 times the population risk. However, because the BRCA1 and BRCA2 gene mutations are rare they account for only a very small proportion of all breast cancers, whereas these common variants, despite their low penetrance, together are implicated in a much larger proportion of breast cancer cases. This complexity is now beginning to be explored in genome-wide association studies. What is emerging from these studies is a picture of just the first few of these common genetic variants involved in susceptibility in the population. These susceptibility alleles act together and are likely to interact with the environment, but currently the synthesis of all these risk factors is not possible to create an overall individual risk.
However, as our understanding of this genetic landscape improves there may be a role in the future for genotyping at population level to guide screening and prevention programmes.