Diagnostic yield of germline genetic testing for early-onset colorectal cancer in a safety-net healthcare system.

Abstract

88 Background: Germline genetic testing (GGT) is recommended for all individuals with early-onset colorectal cancer (eoCRC), defined as diagnosis before age 50. The diagnostic yield of GGT in eoCRC patients has been reported to range from 16-25%, although these estimates are largely derived from studies in resource-rich settings with limited diversity of patient ancestry. The aim of this study was to characterize the results of GGT in a predominantly Hispanic cohort of patients with eoCRC evaluated in a safety-net healthcare system. Methods: Clinical data were retrospectively analyzed from patients referred to an adult genetics clinic in a safety-net healthcare system (Harris Health System in Houston, TX) from 2015-2024. Patients with a history of eoCRC who were <50 years old at the time of clinical genetics evaluation were included. The scope of each patient’s GGT was classified as either “focused CRC” testing (if limited to genes associated with hereditary CRC) or “expanded cancer” testing (if encompassing genes related to other cancers). The primary outcome measure was diagnostic yield, defined as the proportion of eoCRC patients with a likely pathogenic or pathogenic germline variant (PGV) in a gene associated with hereditary CRC. Among those with a positive result, family history (FH) was reviewed to determine if they would have met NCCN criteria for GGT prior to eoCRC diagnosis. Chi-square tests were used to compare diagnostic yield by sex, ethnicity (Hispanic vs non-Hispanic), and testing strategy (focused CRC vs expanded cancer). Results: 125 patients (74.4% Hispanic, 16.0% Black, 5.6% non-Hispanic White, 4.0% other) with eoCRC (median age at diagnosis: 41 years) were offered GGT, of whom 87.2% (n = 109) completed testing. Overall, 22.0% of all tested patients harbored a PGV in a CRC-associated gene, of whom 58.3% would have met FH-based criteria for GGT prior to their eoCRC diagnosis. Most of the identified PGVs (70.8%) occurred in Lynch syndrome genes ( MLH1 = 10; MSH2 = 4; MSH6 = 2; PMS2 = 1) with hereditary polyposis genes accounting for the remainder ( APC = 3; biallelic MUTYH = 1; STK11 = 1; BMPR1A = 1; SMAD4 = 1). Diagnostic yield did not differ by sex, ethnicity, or testing strategy (p > 0.05 for all). 29.4% of all tested patients had at least one variant of uncertain significance in a cancer-associated gene. Conclusions: In this predominantly Hispanic cohort of patients treated in a safety-net healthcare system, the diagnostic yield of GGT for eoCRC was 22%. Over 40% of those with a positive result would not have met family history-based criteria for testing prior to CRC onset, supporting consideration of broader or even universal GGT of high-penetrance genes. Ensuring access to guideline-informed genetic testing, including in resource-limited settings, is essential to facilitate timely diagnosis of actionable genetic variants.