EP064: Consumer-initiated genetic testing identifies individuals predisposed to multiple hereditary cancer syndromes

Abstract

Cancer is a leading cause of death and suffering worldwide, affecting millions each year with the impact reverberating beyond just the person with the diagnosis. Historically, relevant personal and family histories of cancer have been necessary prerequisites for the recommendation of genetic testing to uncover the diagnosis of a hereditary cancer syndrome. However, there is mounting evidence that many people without relevant histories harbor pathogenic or likely pathogenic variants in hereditary cancer genes that put them at high risk of developing cancer during their lifetime. Recently, there has also been an increase in genetic testing in healthy populations through at-home consumer-initiated genetic testing (CIT), which allows for a genotype-first approach to testing, rather than a traditional route of undergoing genetic testing following a cancer diagnosis. Based on this influx in testing in previously unstudied healthy adult populations, and the prevalence of pathogenic variants in genes associated with hereditary cancer genes at a population level, there is potential for the occurrence of biallelic events to be higher than previously understood. While there is some disparate information in the literature describing occurrences of biallelic pathogenic variants in disease and high risk cohorts, we aim to expand on that limited pool, and examined a population of healthy adults seeking CIT who are identified to have multiple pathogenic variants associated with multiple hereditary cancer syndromes. A retrospective case review of individuals who received results for a CIT healthy adult panel over the course of 6 months from Nov 2020-June 2021 was conducted to determine the number of cases that tested positive for more than one pathogenic or likely pathogenic variant in two different cancer genes. The CIT NGS testing panel included the following genes associated with hereditary cancer: ATM, BRCA1, BRCA2, PALB2, APC, BMPR1A, MLH1, MSH2, MSH6, PMS2, MUTYH, POLD1, POLE, SMAD4, CHEK2, and STK11. Individuals who tested positive for two variants within the same gene or for two variants causing the same hereditary cancer syndrome were excluded from this analysis. All individuals reside in the U.S. and are at least 18 years of age. Only pathogenic and likely pathogenic variants were reported. Personal and family history information was self-reported at the time that the test was ordered and further clarification of those histories was provided during post-test genetic counseling sessions. While proactive outreach, including emails and one phone call was completed for each individual to encourage them to schedule a genetic counseling consultation, not all individuals opted to have genetic counseling. There were a total of 100,436 individuals from Nov 2020-June 2021 that underwent CIT NGS panel testing which included all high risk cancer genes listed in the methods. Of those, 2,977 (3%) individuals were identified to have at least one positive finding in a high risk cancer gene. There were 43 individuals (0.04% of total population and 1% of positive cases) who tested positive for two distinct hereditary cancer syndromes, meaning a pathogenic or likely pathogenic variant in two different genes associated with increased cancer risk. In this cohort of 43 individuals, ages ranged from 18-years-old through 66-years-old, with a reported sex breakdown of 18 males and 25 females. Only 13 out of the 43 cases (30%) identified would have met NCCN criteria to qualify them for clinical testing. Therefore, 70% of individuals would not have qualified for clinical genetic testing. This study demonstrates that healthy individuals without relevant histories can harbor pathogenic variants in genes associated with multiple hereditary cancer syndromes, and that the majority of these individuals would not have qualified for clinical testing based on current NCCN criteria. This study sets the framework for future research into the occurrence of biallelic pathogenic variants conferring risk for multiple cancer syndromes at a population level. Future characterisation of this group may be able to help determine more precise risk figures, a better understanding of the effect of gene-gene interaction on risks, and further the discussion of increased access to genetic testing to ensure timely preventative medical decisions can take place.