Soon, we will all be VOUS – The need for a cancer oriented ENCODE program

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

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How do mutations arise in RNA viruses?

As we understand more about the human genome, it becomes equally important to understand its relationship with the genomic environment. In the case of RNA viruses such as SARS, Hepatitis C or Influenza, an inappropriate interaction with a viral genome can result in death. The human genome defends itself by to engineering specific immunological factors (T cells, antibodies) that selectively target viral antigens. However, RNA viruses can rapidly mutate, escape immunological defenses and even become resistant to therapeutic drugs. A contemporary example is the ability of the Flu virus to mutate a single amino acid, rendering it resistant to Tamiflu. Most of our fundamental knowledge in genomics and molecular biology has accrued from the study of model virus systems. However, there is a remarkable lacuna in our understanding of the molecular mechanisms of RNA viral mutation. The current dogma is that such errors arise because of the lack of a proof reading function during replication. In short, a default concept. However, given that it is advantageous to mutate, one suspects that there are viral factors that actively catalyze mutagenesis. Perhaps the somatic hypermutation of the immunoglobulin genes is an attractive metaphor. In any event, much more attention should be devoted to investigating these mechanisms. It would be tragic if the current H1N1 pandemic further illuminates our lack of knowledge

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Novel connections between the “old” protein world and the “ new” RNA world.

Amidst the increasing attention given to the economical sequencing of the human genome, one inconvenient truth remains largely ignored. Virtually all of biomedical science and pharmaceutical industry has focused on merely 2% of the genome, the segment of the genome that encodes proteins. Until recently the other 98% had been somewhat famously described as Junk. However, it is now clear that non-coding RNAs such as microRNA, esiRNAS, piRNAs that reside in the “junk”, have critical cellular functions.
It has been known for a long time that it is the noncoding segment of the genome that is most variable between human individuals. Thus, when the deluge of human sequence information arrives, the successful interpretation of these variants will be a challenge. However, noncoding RNA genes appear to exert their effect by their complementarity to other nucleic acid sequences and therefore their interactions are much more predicable than their protein counterparts
For example investigators have begun to explore the possibility that variants in human sequence may affect phenotype by modulating microRNA target sites in messenger RNA. Indeed, Dr Francis Collins, the new NIH director has recently written a timely and compelling review of this area.
Importantly, it is critical to realize that these human sequence variants are “plastic”. Their ability to increase the risk of disease is not “cast in stone’ but will depend upon the expression of the noncoding RNA. It is hoped that an understanding of the factors that regulate such noncoding RNAs will identify changes in life style that may prevent disease.