Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management

Abstract

BackgroundMultigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing.MethodsWe include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope’s Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C.ResultsIf historically high risk genes only were included in the panels (BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time.ConclusionThese figures and cases stress the importance of adequate pre-test counseling in anticipation of higher percentages of positive, VUS, unexpected, and ambiguous test results. Test result ambiguity can be limited by the use of phenotype-specific panels; if found, multiple resources (the literature, reference laboratory, colleagues, national experts, and research efforts) can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient’s personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels.

Genetics in the 21st Century: Implications for patients, consumers and citizens

“…An increase in the scale of testing available inevitably also means an increase in the range of results returned – many of which, in the current climate, can only be interpreted as ambiguous or uncertain (due to the embryonic nature of our knowledge of this field) 9 . Such ’Variants of Unknown Significance’ are results where the meaning is unclear and are more likely to be discovered when multiple genes are tested for at once 10 .…”

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

“…Moderately penetrant genes confer a lifetime cancer risk of 20% to 50% or a 2 to 4-fold increase above the general population risk 29 . Low-or unknownpenetrance genes may have limited or conflicting evidence 2,4,5 . Table 1 provides examples of genes that may be included in each group.…”

“…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.…”

“…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 . While the ability to test for multiple cancer susceptibility genes at one time is attractive and even exciting, this new technology brings challenges that must be addressed in the pre-test genetic counseling session.…”