Abstract
Multigene 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. We 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. If 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. These 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.
Highlights
National guidelines include discussion of hereditary cancer panels inclusive of multiple genes as a potentially cost- and time-effective alternative to sequentially testing multiple single genes associated with a given phenotype; or when atypical family presentations, or limited family structure make it difficult to use family history alone to determine the most appropriate gene(s) to test [17, 18]
Challenging Multigene Panel Genetic Counseling Risk Assessment Cases Colorectal Cancer in CDH1 Case 1 is a 48-year-old male of Chinese ancestry diagnosed with metastatic left-sided adenocarcinoma of the colon at age 45
His family history was devoid of other cancers (Figure 3)
Summary
An interdisciplinary medical practice that employs a growing arsenal of genetic and genomic tools to identify individuals and families with inherited cancer risk [1], genetic cancer risk assessment (GCRA) enables informed choices about cancer screening [2,3,4], surgical [5,6,7,8,9], and chemopreventive risk management options [10,11,12,13,14], as well as genetically targeted cancer treatment therapies [15, 16]. Moving beyond single-gene testing has unveiled new challenges to the clinician involved in providing GCRA. The prevalence of variants of uncertain significance (VUS), unexpected findings, such as “off-phenotypic-target” gene mutations, and pathogenic findings in low and moderate risk genes challenge the established counseling repertoire. The purpose of this article is to illustrate some of the challenges and opportunities associated with expanded hereditary cancer panel tests, many of which include both well-characterized and lesser known cancer-associated genes. Multigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. 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
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