Breast cancer genetics: why don't we know more?

A recent article by Michael Stratton and Nazneen Rahman in the journal Nature Genetics reviews "the emerging landscape of breast cancer susceptibility."

Breast cancer has a public image as a terrifying disease, suddenly striking down previously healthy women in their prime. Although the risk of death from breast cancer is in fact generally exaggerated in the public mind (a woman's risk of contracting breast cancer before the age of 60 is just 3%; in terms of life-time risk, women are far more likely to die from heart disease), the disease nonetheless has horrific effects on sufferers and their families.

It has long been known that the risk of breast cancer is influenced to some degree by genetic factors: first-degree female relatives of women who have contracted breast cancer have twice the risk of contracting the disease compared to the general population. In the mid-1990s, researchers discovered that women who carried mutations in either of two genes - BRCA1 and BRCA2 (BReast CAncer 1 and 2) - were subject to a massively increased risk of breast cancer, about 10 to 20 times higher than the risk for non-carriers. In real terms, that means that women who carry one of these mutations are at a 30-60% risk of developing breast cancer before the age of 60, compared to 3% in the general population. However, these mutations are rare, being carried by only one in 1,000 individuals in the UK.

Since the discovery of BRCA1 and BRCA2, four other genes have been found in which mutations confer high risk of breast cancer (and other cancers), but again these mutations are rare. The low frequency of these mutations in the population mean that although they have high predictive value for the few individuals who carry them, they are not particularly informative for the population as a whole: taken together, these six genes account for less than 20% of the total familial risk of breast cancer.

So where does the remaining 80% of familial risk come from?

It turns out that this risk comes from a whole range of other genetic variations, most of which are yet to be identified. Each genetic variation differs in terms of its frequency within the population and its penetrance (that is, the proportion of individuals carrying the mutation who actually go on to develop breast cancer), but the mutations that increase the risk of breast cancer can be classified into three rough and overlapping categories: rare variants with high penetrance (like BRCA1 and BRCA2); rare variants with moderate penetrance; and common variants with low penetrance.

Finding the second and third class of variants is hard, as I'll explain in a series of upcoming posts. The new techniques developed to find these types of variants are now becoming standard approaches in modern human genetics, and with good reason: they are our only hope of identifying the genetic risk factors that underlie most of our risks of common diseases, including not only breast cancer but also heart disease, diabetes, arthritis, and a host of other ailments.


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