Not for everyone
By Carol A. Burke, MD, AGAF, and Brandie Heald Leach, MS
Multigene panel testing (MGPT) takes advantage of next-generation sequencing (NGS) a non-Sanger-based DNA sequencing technology which has revolutionized genomic research and clinical care because it can be run quickly, is lower cost than Sanger sequencing, can sequence an entire genome or exome, or specific genes of interest. Currently, cancer gene panels (disease specific or pan-cancer) are commonly utilized.
Approximately 10% of colorectal cancers (CRCs) are heritable because of a germline pathogenic variant (PV), most commonly in Lynch syndrome genes. Identification of patients with hereditary CRC is important because they are at greatest CRC and extracolonic cancer risk, benefit from aggressive cancer surveillance. and when indicated may need prophylactic surgery of at-risk organs, require multidisciplinary care, and may have at-risk family members who need testing.
Red flags regarding family cancer history may allow clinical inference as to the cause of CRC and direct who is offered germline testing. These include young age of cancer (age less than 50), synchronous or metachronous cancers, multiple relatives with CRC or extracolonic cancers, and cumulative lifetime numbers of adenomas or hamartomas. While overt clinical manifestations can be specific for predicting the causative gene defect, such as Amsterdam criteria for Lynch syndrome or numerous adenomas at a young age in familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations. While family pedigrees with a phenotype that meets clinical criteria, such as Amsterdam II, can be very specific (although less sensitive) for predicting Lynch syndrome, or overt clinical manifestations such as 100 adenomatous polyps in an individual by the age of 40 is highly suggestive of familial adenomatous polyposis, overlap can occur between syndromes and single gene testing has its limitations.
The current standard of care for patients with CRC is germline testing after assessment of tumor mismatch repair (MMR) proficiency by microsatellite instability (MSI) testing and/or immunohistochemistry (IHC). Broadly, tumors that show high levels of MSI and or loss of expression of MMR proteins (not attributed to MLH1 promoter hypermethylation or double somatic mutations/loss of heterozygosity) are considered MMR deficient (MMRd) and suggestive of Lynch syndrome. MMRd directs treatment (immune check point inhibitors) and is a hallmark of Lynch syndrome as 95% of Lynch syndrome–related CRCs are MMRd.
The utility of MGPT in individuals with CRC can be inferred from two studies. In both, a 25-gene pan-cancer panel test was performed. In the first, 1,058 unselected individuals with CRC at a mean age of 56 were assessed regardless of MMR status; 9.9% were diagnosed with moderately (4.7%) or highly penetrant (5.2%) PV.1 In these individuals with CRC, 31% were diagnosed with Lynch syndrome and nearly all Lynch syndrome patients had MMRd tumors and met criteria for germline testing for Lynch syndrome; 22% of patients had other high-penetrance PV found, the majority lacking clinical features consistent with the PV. The second study,2 tested 450 patients with CRC diagnosed under the age of 50. Germline PV were detected in 16%. The majority of patients with an MMRd tumor were diagnosed with Lynch syndrome. Eight percent of patients with an MMR-proficient tumor had a PV detected. Nearly one-third did not meet clinical criteria for testing. Germline variants of uncertain significance (VUS) were noted in approximately 32% of patients in both studies. These data support the current standard of tumor assessment for MMRd, followed by Lynch syndrome germline testing as directed by IHC.
While MGPT for patients with CRC is feasible, the high rates of VUS, detection of moderate and low penetrance PV for which no clinical guidance exists, and dearth of evidence on penetrance and cancer risk attributable to incidentally found PV, need consideration. Prior to germline testing, patients and providers must understand potential testing outcomes, possible detection of incidental findings and VUS, and how each influence patient cancer risks and management. The commercial genetic testing companies accumulate information on VUS over time and reclassify the significance of the finding, but this process could take months to years. Providers ordering genetic testing must have a system to inform the patient when a VUS is reclassified.
Pre- and post-test genetic counseling, ideally by an individual with understanding of medical genetics, should be offered, including caveats, risks, benefits, and alternatives to germline testing, a plan for results disclosure, including to family members, and a plan for follow-up care. Patients with uninformative findings and VUS need to be followed as technology and research evolve. Patient preferences regarding genetic testing need to be considered. There still remains stigma and fear associated with genetic testing. Despite protections from the Genetic Information Non-Discrimination Act, many patients remain fearful of genetic discrimination. A genetic diagnosis comes with the burden that it reveals not only information about the patient’s risks, but potentially also his/her family members’ risks. These are valid patient concerns that need to be vetted and addressed.
Selection of correct testing strategy is important. A patient with a known PV in the family might benefit most from single-site analysis for the family mutation. For a patient with an affected relative who had negative genetic testing, additional genetic testing for that patients is unlikely to be beneficial. For a patient with no known PV in the family who meet genetic testing criteria, a cancer gene panel should be considered. However, guidance on which MGPT to order is lacking in professional guidelines and often left to the discretion of the provider and patient. Utilization of a “disease specific panel” (i.e., a panel of genes related to CRC risk) is useful for understanding the cause of the patient’s disease and guiding treatment, screening, and cascade testing while minimizing the number of VUS identified. Pan-cancer gene panels increase diagnostic yield, but include identification of PV in genes unrelated to phenotype or more poorly described risk and management recommendations and have a higher rate of VUS.
Finally, the cost of MGPT to the health care system needs to be considered. Despite dropping costs, the process of genetic counseling and testing remains expensive and will rise if and when testing is expanded to all patients with CRC.
MGPT is not for everyone.
1. Yurgelun MB et al..
2. Pearlman R et al.
Dr. Burke is with the department of gastroenterology, hepatology, and nutrition, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic; Ms. Leach is with the Center for Personalized Genetic Healthcare, Sanford R. Weiss Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic. Dr. Burke has no conflicts of interest, Ms. Leach serves on the advisory board of Invitae.