BRCA sequencing of tumors: understanding its implications in the oncology community.

Abstract

In the current era of personalized medicine, much more information can be gleaned through genetic testing and tumor sequencing. Unfortunately, this comes at a price of obtaining results that may beget more uncertainties. Sequencing for mutations on tumor samples is increasingly performed, more commonly to guide treatment for oncology patients, and occasionally as a proxy for germline testing when the ideal index patient to initiate genetic testing in a family at risk for hereditary cancer syndrome is no longer alive. Next-generation sequencing (NGS) involving tens to hundreds of genes as a testing platform is being used more routinely in the clinic now. However, one should keep in mind that the larger number of genes included in an NGS panel will yield a correspondingly higher probability of finding an incidental germline pathogenic mutation, which will have both clinical and ethical implications for patients and their families. The probability of identifying a tumor pathogenic BRCA1/2 variant is about 3-4%, with the majority (~80%) being germline in nature; thus, patients should be counselled accordingly prior to having their tumor samples sequenced. On the flip side, caution should be exercised when tumor sequencing is intended to be a surrogate for germline testing. This is because false negative rate is high at ~30%, making it an inadequate tool to sufficiently dismiss the presence of a germline BRCA1/2 mutation, especially in a setting where there is already a high clinical suspicion for a hereditary condition.