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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: genetic counseling; hereditary breast cancer; hereditary cancer panel; hereditary colon cancer; multigene panels; next-generation sequencing.

Figure 1

General characteristics of genetic cancer risk groups. Genetic risk categories are shown with an adjacent matched color descriptor noting the general features specific to each risk tier. Quantification of risk with a categorization of genes in each tier is provided in Table 1. Clinical utility (arrow) increases with higher cancer risk predisposition. The arrow gradient denotes the potential significant overlap between the tiers. Clinical utility and refined risk scores may improve in the future, especially for low and moderate risk genes (19). Penetrance, actionability, and implications for family members have been simplified for conceptual use.

Figure 2

Clinical cancer genetics community of practice experience with multigene panel tests. 403 results of 348 commercial multigene panel tests ordered by Clinical Cancer Genetics Community of Practice clinicians between January 1, 2014, through October 1, 2014 are depicted. “VUS” means variant of uncertain significance. “Uninformative” refers to negative panel testing results. “Inconclusive” refers to the laboratories inability to classify the result into other categories at the present time. The plus symbol (+) denotes that six patients had mutations in ≥1 gene. Asterisk (*) denotes that 35 patients had ≥1 VUS. The side table shows the number of individual positive gene mutations found. (φ) denotes that five MUTYH cases were monoallelic, whereas one case was biallelic.

Figure 3

Proband (arrow head) with colorectal cancer (CRC) and a CDH1 monoallelic mutation. Note the large extended family without cancer. There was no known gastric cancer even in the extended family. Please see associated vignette for more details.

Figure 4

Family with a pathogenic PALB2:c.3113G > A (p.Trp1038Ter) mutation (+) in the proband (arrow head) and daughter. CLL, chronic lymphocytic leukemia; Br, breast cancer. PALB2 mutations have not been associated with CRC, GIST, or colon polyps (polyps, number unknown). Please see associated vignette for more details.

Figure 5

Family with a suspected deleterious CHEK2 allele that does not track as expected with the family history of cancer. Breast cancers (Br) with ages are shown. The CHEK2 mutation (+) in the denoted proband (arrow head) did not track as expected with one of the maternal half-sisters (−). Testing for other family members was not available. Please see associated vignette for more details.