The Evolution of Cancer Risk Assessment in the Era of Next Generation Sequencing

Abstract

Cancer genetics professionals face a new opportunity and challenge in adapting to the availability of cancer genetic testing panels, now available as a result of Next Generation Sequencing (NGS) technology. While cancer panels have been available for over a year, we believe that there is not yet enough data to create practice guidelines. Despite this, a year of experience allows us to provide our opinion on points to consider as cancer genetic counselors incorporate this testing technology into genetic counseling practice models. NGS technology offers the ability to potentially diagnose hereditary cancer syndromes more efficiently by testing many genes at once for a fraction of what it would cost to test each gene individually. However, there are limitations and additional risks to consider with these tests. Obtaining informed consent for concurrent testing of multiple genes requires that genetics professionals modify their discussions with patients regarding the potential cancer risks and the associated implications to medical management. We propose dividing the genes on each panel into categories that vary by degree of cancer risk (e.g. penetrance of the syndrome) and availability of management guidelines, with the aim to improve patient understanding of the range of information that can come from this testing. The increased risk for identifying variants of uncertain significance (VUS) when testing many genes at once must be discussed with patients. Pretest genetic counseling must also include the possibility to receive unexpected results as well as the potential to receive a result in the absence of related medical management guidelines. It is also important to consider whether a single gene test remains the best testing option for some patients. As panels expand, it is important that documentation reflects exactly which genes have been analyzed for each patient. While this technology holds the promise of more efficient diagnosis for many of our patients, it also comes with new challenges that we must recognize and address.

Genetic evaluation and testing for hereditary forms of cancer in the era of next-generation sequencing

“…Not all individuals wish to pursue testing and not all family and medical histories warrant testing. Genetic testing should be offered however, when the following conditions are met 3,8,11,16 : (1) the individual has a personal or family history suggestive of a hereditary cancer syndrome; (2) test results can be adequately interpreted; (3) test results will influence the medical management of the individual or their family members; and (4) testing is accompanied by informed consent.…”

“…The process of informed consent for genetic testing for inherited cancer susceptibility is well described 3,11,16,28 . In order for an individual to give fully informed consent for genetic testing, the following educational elements must be provided: (1) information on the specific gene(s) or gene mutations(s) being tested including a description of associated cancers and other potential health risks; (2) inheritance patterns associated with genes being tested.…”

“…In the context of a pre-test genetic counseling session it would be impossible to thoroughly review all of the potential cancer and health risks associated with individual genes on 10, 20, or 100 gene panels. Therefore modifications to the existing informed consent process have been proposed 3,4 . Genes on NGS cancer panels may be classified into 3 groups based on penetrance: high risk, moderate risk and low or unknown risk [2][3][4][5] .…”

“…Therefore modifications to the existing informed consent process have been proposed 3,4 . Genes on NGS cancer panels may be classified into 3 groups based on penetrance: high risk, moderate risk and low or unknown risk [2][3][4][5] . Opinions vary, but generally highpenetrance genes are considered to confer a lifetime risk for cancer of 50% or greater.…”

“…It is now possible to evaluate the entire differential diagnosis for a patient and family with a single laboratory specimen. This decreases the time to a potential diagnosis and reduces testing fatigue for patients, families and providers 2,3 . The knowledge gained through the use of NGS is increasing our understanding of the natural history of hereditary cancer syndromes and contributing to the expanding phenotypes associated with individual cancer susceptibility genes 4,5 .…”