Although the aim of the overview was to present empirical risk estimates, these estimates do raise some interesting issues with regard to the genetics of breast cancer. Two studies have estimated that mutations in the BRCA1 and BRCA2 genes only account for approximately 15% of the excess familial risk of the disease [5, 6], while the contribution of the other known breast cancer susceptibility genes (TP53, PTEN, CHK2 and ATM) is even smaller [7]. The contribution of known genes is higher than this in certain populations where specific BRCA1 or BRCA2 mutations have become common as a result of founder effects. These populations include Iceland, Ashkenazi Jewish populations and parts of Poland. In most Western populations, however, the observed familial risks are largely the result either of other genes or of nongenetic familial risk factors. While the possibility of the latter cannot be definitively ruled out, results from twin studies suggest that the majority of the familial risk is in fact genetic in origin [8, 9]. (Since adjustment for known reproductive and other breast cancer risk factors had essentially no effect on the familial risks, nongenetic contributors to the familial risk, if there are any, must presumably be unrelated to the known risk factors.)
The absence of substantial difference in risk by type of affected relative (i.e. affected mother versus affected sister) suggests that the important genes are likely to act dominantly or additively on risk, but not to act recessively (recessive susceptibility genes give rise to higher risks in siblings than in parents or offspring). Some studies using a family-based cohort approach have found higher risks in siblings, and these notably include studies of cases diagnosed at a particularly young age [10, 11]. These results do not necessarily conflict with the overview, since the risk estimates from the overview are imprecise at young ages. Conversely, it may be that the higher risk to siblings in the cohort studies is due at least in part to cohort effects on background incidence rates, and to the artefactually low rate of breast cancer in mothers who are, by definition, parous.
The pattern of risk by the number of affected relatives is also revealing. The fact that the risk increases progressively with the number of affected relatives suggests the effect of a fairly large number of genetic risk groups, consistent with, for example, a polygenic model as proposed by Antoniou et al. [12]. The trend in relative risk with age suggests that (like BRCA1 and, to a lesser extent, BRCA2) some or all of the susceptibility genes involved are likely to confer a higher relative risk at young ages.
Finally, the similarity of the risk ratios for other risk factors in women with and without a family history suggest that these risk factors act to a similar extent in women at any level of genetic susceptibility. Of course, one cannot necessarily assume that this will hold for carriers of particular susceptibility mutations. Studies of BRCA1 and BRCA2 mutation carriers have shown that early menopause does have the expected protective effect in these groups [13], but the effects of other risk factors such as parity have not been definitively established [14, 15].
What are the implications for genetic counselling? Perhaps the most important is that the absolute risk of breast cancer in women with just one affected relative is relatively modest, even when the relative is diagnosed at a young age (the authors estimate a cumulative risk of 16% by age 80 years for women with a relative diagnosed younger than age 40 years). The risks associated with having larger numbers of affected relatives are more substantial, and referral to cancer genetics clinics should reflect this. The results of the present study also imply that the effects of reproductive and hormonal risk factors could be usefully incorporated into genetic counselling. Since the effects of family history and these other risk factors on breast cancer risks appear to combine in roughly multiplicative fashion, the absolute effects of risk factors in individuals with a strong family history can be substantial.