Somatic mutational profiling identifies aggressive and indolent disease phenotypes in well-differentiated pancreatic neuroendocrine tumors.

Integration of biomarkers into clinical management of well-differentiated pancreatic neuroendocrine tumors (PNETs) remains limited due to disease rarity and heterogeneity. By utilizing publicly available genomic databases, we've established a large cohort of well-differentiated PNETs for study, focusing on somatic mutations and disease subgroup stratification through a modified targeted sequencing approach. A total of 434 patients, representing 310 primary tumors and 124 metastatic tumors, from nine publicly available genomic studies were included for study. A targeted sequencing panel consisting of 261 genes was applied across the cohort to establish somatic variant profiles for each patient. Patients were further allocated into established and novel molecular subgroups for additional investigation. MEN1 remains the most frequently mutated gene in both primary and metastatic tumors (41.9%, both). Within subgroup stratification, ATRX and DAXX mutations were not associated with a survival deficit in the metastatic setting, contrary to prior reports. TP53 mutations, traditionally associated with neuroendocrine carcinoma, remained prevalent occurring in 5.5% and 19.4% of primary and metastatic tumors, respectively. An additional 4.2% of primary tumors and 9.7% of metastatic tumors harbor mutations in either KRAS or SMAD4 that are more typically associated with pancreatic adenocarcinoma. TP53 mutations were associated with metastasis, suggesting the presence of a more aggressive disease phenotype. Somatic variants serve as prognostic biomarkers in well-differentiated PNETs. Profiling of TP53, KRAS, or SMAD4 status may aid in identifying aggressive subtypes of disease. Additional evaluation of the utility of targeted tumor sequencing to guide PNET treatment is warranted.