The 2012 CTRC-AACR San Antonio Breast Cancer Symposium, 4-8 December
Influence of low penetrant factors on overall cancer risk
Professor Douglas Easton – Cancer Research UK Genetic Epidemiology Unit, Cambridge University, UK
We know now that there are a large number of different genetic variants that are associated with breast cancer risk. In the early days we found the high risk genes like BRCA1 and BRCA2 where there are mutations which give high risks of breast cancer and other cancers and they’re widely used in clinical genetics practice. But they’re only part of the story and what we’ve discovered over the last five years or so is that there’s a very large number of other genetic variants, most of which are quite common in the population, that each somewhat change the risk of breast cancer. If you put them all together you can identify women who are at quite significantly higher or lower risk of the disease.
These are low penetrants?
The high risk genes are BRCA1 and BRCA2, they each give risks where a woman is likely to develop the disease, whereas these low penetrance genes or mutation variants, they only change a woman’s risk a little bit individually. It’s only really if you consider them in combination that the risk difference becomes significant.
What have you started to identify?
We’ve now, just over the last year really, through one very large experiment called the iCOGS experiment, we’ve increased the number of these low penetrance variants from about thirty to about eighty. These are variants throughout the genome in a wide variety of different regions with different genes associated with them. We’re only really beginning to understand a little bit about how they work but we’re certain that they each have a small but significant influence on risk.
Have you found any relationship between specific sub-types of cancer?
There’s definitely relationships with subtypes so in particular some variants are more associated with oestrogen receptor positive disease; some are more associated with the oestrogen receptor negative disease and some are more associated with both. So there are three different classes of variant and those presumably tell us something about the pathways in which they operate.
What are the implications for an individual’s risk assessment?
That’s the idea. So you can essentially build up a profile of someone’s risk based on the combination of all the variants they have and to make it really useful you really want to put that together with other risk factors, so reproductive factors, breast density and so forth. So that’s how we envisage this information really being used to identify higher and lower risk individuals and those might then be targeted by, for example, changing the screening programme so that women at the higher risk end would get more intensive screening perhaps, screening starting at an earlier age or more frequent or screening with MRI. Women at the low risk end probably don’t need to be screened as frequently. At the moment BRCA1 and 2 mutations are only screened in women who have quite a strong family history because it’s relatively expensive. I think going forward it’s quite possible that those high risk genes might also be screened for population-wide along with the lower risk polymorphisms and that raises a number of issues about how you would deal with BRCA1 and 2 testing in the population at large but technically I’m sure that would be feasible.
What therapies are there for these types of mutation?
A very important question which we don’t yet know. In some cases we do know what the target gene is likely to be, in most we don’t yet know. Some of those genes are potentially drug targets and so it’s quite possible that these would be a lead in to therapeutics, specific therapeutic interventions. But that’s obviously going to be a long process, it took fifteen years to go from finding the BRCA1 and 2 genes to actually getting to a therapy which was based on them so I suspect it would also take a long time for the low risk polymorphisms to lead to specific treatments.
