A comprehensive target panel allows to extend the genetic spectrum of neuroendocrine tumors.

Abstract

Introduction: Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NETs development continues to expand. Application of targeted gene panels (TGP) in next-generation sequencing (NGS) is a central strategy for elucidating novel variants associated with NETs development.

Methods: In this study, we conducted comprehensive molecular-genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n=26), pheochromocytoma and paraganglioma (PPGL) (n=38), parathyroid adenoma (n=18, including three with insulinoma), and NETs of other locations (n=14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines.

Results: Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mechanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8.

Conclusion: Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs, facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.