Germline pathogenic variants in patients with early onset neuroendocrine neoplasms.

Neuroendocrine neoplasms (NEN) are a rare group of cancers with heterogeneous behavior and mostly of unknown aetiology. Excluding some infrequent hereditary cancer syndromes, the extent and clinical significance of mutations in other cancer predisposing genes (CPG) are not known. We aimed to investigate the frequency of pathogenic and likely pathogenic germline variants (GPV) in known CPGs in young adults with NEN and the clinical and molecular characteristics of these patients. We recruited 108 patients with lung or digestive NEN diagnosed between 18 to 50 years and performed targeted sequencing of 113 CPGs on germline DNA. For some patients, tumor features as loss of heterozygosity (LOH), tumor mutation burden and microsatellite instability were evaluated. GPVs were detected in 17 patients (15.7%). Median age, sex, stage at diagnosis, family history of NEN or any personal history of neoplasm were similar between patients with or without GPVs. GPVs carriers had more gastric (p = 0.084), functioning NEN (p = 0.041), positive family history of cancer (p = 0.015), and exclusively well-differentiated histology. Genes affected were mostly involved in DNA repair (CHEK2, ERCC2, ERCC3, XPC, MSH6, POLE, SLX4), with most GPV found in MUTYH (4 cases). LOH was performed in 8 tumors and detected only in a SLX4 positive case. Overall, our findings indicate a role of inherited genetic alterations, particularly in DNA repair genes, in NENs carcinogenesis in young adults. These patients more often had a family history of cancer and functioning NEN.