The BRCA1/BRCA2 test is now considered the standard of care for identifying breast and ovarian cancer risk. Indeed, women who have been tested for BRCA1/BRCA2 status must view the current discourse on the possible implications of personalized genetic medicine with incredulity. It is very clear that women who inherit a dysfunctional form of the BRCA1 or BRCA2 gene have a much higher risk of developing breast or ovarian cancers. A positive BRCA1/BRCA2 test triggers the individual, their genetic counselor and oncologist to explore drastic preventative measures, such as an oophrectomy or a mastectomy. Regardless of whether or not the patient chooses to undergo surgery, a positive test will prompt regular checkups and greatly increased scrutiny. However it is unfortunate that comparatively little attention has been paid to this area. For example, the correlation between cancer risk and the specific mutation (for example missense or nonsense) has not been clarified. This is likely because the number of individuals that harbor informative mutations are still a small percentage of the total number of breast and ovarian cancer patients. However, to the individual with a mutation, the relevance is immediate and of critical importance. For example, it has recently been discovered in the U.K. that women with mutations in BRCA2 specifically respond to therapy that inhibits the DNA damage response pathway.
But what if test findings tell an individual that they have a variant of unknown significance? Becoming increasingly more common among BRCA1/BRCA2 test results, variants of unknown significance (VOUS), or unclassified variants, give the patient no concrete sense for their cancer risk. For individuals that decide genetic testing is the right route to assess their cancer risk, possessing the knowledge that their BRCA1 gene has a significant mutation may be bad news, but is at least a concrete picture of their cancer risk. Receiving news of a variant of unknown significance that could be inconsequential or life threatening is quite devastating.
This problem is likely to be significantly compounded in the near future. At present, it is only women who have an obvious family history of cancer that are tested, However, it is clear that there is significant public interest in DNA sequence analysis and personalized medicine. The whole scale adoption of whole genome analysis will undoubtedly provide a deluge of new sequence variants. Soon, everyone will be VOUS! The majority of test results that come back will show presence of variants of unknown significance. Importantly most of these variants will reside in the untranslated regions of BCRA1/2 and will influence the expression of BRCA1/2 rather than the structure of the proteins. For these variants, conventional risk assessment will be complicated by the unknown factors (oncogenes, hormones, environmental factors) that will likely modulate the effects of these variants upon the expression of BRCA1/2. Clearly, what is needed is an ENCODE type program, but one that is devoted to finding functional assays that can independently signal the risk of breast and ovarian cancer.
Caroline Meade - Guest Contributor