Germline Cancer Testing in Unselected Patients With Neuroendocrine Neoplasms: A Multi-center Prospective Study

PURPOSE: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected NEN patients remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multi-gene panel testing in a diverse cohort of NEN patients. PATIENTS AND METHODS: Between 2018 and 2024, we enrolled unselected patients with NENs from three Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. RESULTS: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1, CHEK2, MITF, and MUTYH. PGVs were most commonly found in pancreatic NENs (21.8% n=12/55), followed by small bowel NENs (10%, n=2/20), with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including one MLH1 PGV and four MSH2/MSH6 VUS, two of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. CONCLUSIONS: Universal germline testing in unselected NEN patients identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing-regardless of traditional clinical selection criteria.