Multi-Gene Panels—Changing Our Approach to Hereditary GI Cancers
Multi-gene panels can have a significant impact on the successful identification of patients with or at-risk for hereditary gastrointestinal cancers, such as those associated with Lynch syndrome. According to Maria J. Baker, PhD, professor of medicine and genetic counselor, medical geneticist, hematology and oncology, “Multi-gene panels can screen for up to 72 different genes or more, depending on the laboratory, using a single blood sample and eliminating the need for a time-consuming sequence of tests. This can reduce overall costs and shorten the ‘diagnostic odyssey,’ potentially reducing stress for the patient than with traditional sequential genetic testing.”
Patients most likely to benefit from a multi-gene or next generation sequencing panel are those with a personal or family history of cancer that raises concern for multiple genes or cancer syndromes, at the same time. For example, if a patient has a history of 10-20 adenomatous polyps, one should consider testing for attenuated familial adenomatous polyposis (AFAP) and MUTYH-associated polyposis (MAP). Patients with Lynch syndrome, though, can also develop a similar number of adenomatous polyps over their lifetime. Given that Lynch syndrome affects approximately one in 400 individuals, it should also be considered in the differential, especially if there are other Lynch-associated cancers within the family (endometrial, gastric, ovarian, small intestine, urinary tract, etc.). While specialists increasingly order genetic testing to inform medical management and surgical decision-making, large cancer predisposition panels can raise more questions than answers. Therefore, it may be beneficial to identify a local genetic counselor to serve as a useful resource.1
Dr. Baker’s pre-test counseling provides a general overview and clinical implications of testing without going into detail about each specific gene or condition. For patients with positive results, Dr. Baker says, “We meet to explain in-depth their level of increased risk, and what they can do to reduce their risk, such as increased surveillance and prophylactic surgery.” Women with Lynch syndrome may require additional counseling about reproductive options and timing of prophylactic surgery to remove the uterus and ovaries once beyond childbearing.
However, multi-gene panels also present unique challenges. Dr. Baker explains, “The larger the number of genes tested, the higher the likelihood that a variant of unknown significance (VUS) or other uncertain result will show up.” With multi-gene panels, a VUS is reported approximately 20-40 percent of the time, with variant frequency depending on the reported ancestry.1,2
Multi-gene panel test results can raise significant uncertainty where it may be difficult to provide clear guidance about prophylactic surgery or increased surveillance. Dr. Baker adds, “While uncertain results may cause concern, it’s always better to know earlier rather than later, in any cancer situation.”
Multi-gene panel tests increase the likelihood of identifying an underlying genetic predisposition should one exist in the family. And with cancer, knowledge is power.
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”– variant of uncertain significance. “Uninformative”– negative panel testing results. “Inconclusive”– the laboratory’s 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. (j) denotes that five MUTYH cases were monoallelic, whereas one case was biallelic. Courtesy of Slavin TP, Niell- Swiller M, Solomon I, Nehoray B, Rybak C, Blazer KR and Weitzel JN. (2015) Clinical application of multigene panels: challenges of next-generation counseling and cancer risk management. Front. Oncol. 5:208. doi: 10.3389/fonc.2015.00208
- Cragun D, Radford C, Dolinsky J, Caldwell M, Chao E, Pal T. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clinical Genetics. 2014;86(6):510-520. doi:10.1111/cge.12359.
- Susswein LR, Marshall ML, Nusbaum R, Vogel Postula KJ, Weissman SM, Yackowski L, Vaccari EM, Bissonnette J, Booker JK, Cremona ML, Gibellini F, Murphy PD, Pineda-Alvarez DE, Pollevick GD, Xu Z, Richard G, Bale S, Klein RT, Hruska KS, Chung WK. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. GENETICS In MEDICINE. December 17, 2015 [Epub ahead of print] doi:10.1038/ gim.2015.166.