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 NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET 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 mecanisms 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.

Keywords: Genetic testing; Insulinoma; Neuroendocrine tumors; Parathyroid adenoma; Pheochromocytoma; Target gene panel.

Fig. 1.

Representative morphologic samples of the described types of tumors. a Insulinoma (HE, original magnification, ×100) (variant in KLF11). b Pheochromocytoma (HE, original magnification, ×100) (genotype-negative). c Parathyroid adenoma (HE, original magnification, ×100) (variant in RET). d Growth hormone-secreting pituitary adenoma (HE, original magnification, ×100) (genotype-negative). e Lung NET (HE, original magnification, ×100) (variant in APC).

Fig. 2.

Flowchart of the experimental design and genetic findings in different groups. pts, patients; NGS, next-generation sequencing; TGP, targeted gene panel; P, pathogenic; LP, likely pathogenic; VUS, variants of unknown significance. *Three patients are doubled in insulinoma’s and parathyroid adenoma’s group 1; **three variants are doubled in insulinoma’s and parathyroid adenoma’s group 1.