Prevalence of Germline Pathogenic RET Variants in a Pan-Cancer Patient Population

PURPOSE Germline likely pathogenic or pathogenic variants (LP/PV) in the RET proto-oncogene account for approximately 25% of medullary thyroid cancers (MTCs). Depending on the variant, individuals with RET LP/PV can have > 70% lifetime risk for MTC or C-cell hyperplasia, an MTC precursor. We assessed prevalence and genotype-phenotype correlations of RET LP/PV in a pan-cancer population undergoing agnostic multigene germline cancer genetic testing. METHODS Patients with cancer at Memorial Sloan Kettering Cancer Center provided informed consent to Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a paired tumor-normal genomic sequencing protocol (ClinicalTrials.gov identifier: NCT01775072 ) from 2015 to 2023. Consent included multigene germline testing inclusive of RET . LP/PVs in RET were categorized per standardized MTC risk levels. Clinical data, including family history, surveillance results, and pathology, were extracted from medical records. RESULTS Twenty-one of 31,866 patients harbored an LP/PV in the RET gene, with the most common variant being p.Val804Met (n = 10) of moderate risk. Although six patients had a personal history of MTC, 15 of 21 patients (71%) had neither a personal nor a family history of MTC. Of the 15, nine underwent endocrinology high-risk surveillance, with five patients deciding to proceed with thyroidectomy due to abnormal surveillance findings. Pathologic findings consisted of isolated C-cell hyperplasia only (n = 1), microMTC and C-cell hyperplasia (n = 2), stage I MTC and C-cell hyperplasia (n = 1), and stage IVA MTC (n = 1). CONCLUSION In this pan-cancer cohort, 71% of RET LP/PV findings were incidental, with no prior personal or family history of MTC. High-risk surveillance and potential thyroidectomy are warranted in patients with an incidental germline RET LP/PV finding due to high rates of precursor lesions and MTC even among these patients.