Whole-exome sequencing of calcitonin-producing pancreatic neuroendocrine neoplasms indicates a unique molecular signature.

INTRODUCTION

Calcitonin-producing pancreatic neuroendocrine neoplasms (CT-pNENs) are an extremely rare clinical entity, with approximately 60 cases reported worldwide. While CT-pNENs can mimic the clinical and diagnostic features of medullary thyroid carcinoma, their molecular profile is poorly understood.

METHODS

Whole-exome sequencing (WES) was performed on tumor and corresponding serum samples of five patients with increased calcitonin serum levels and histologically validated calcitonin-positive CT-pNENs. cBioPortal analysis and DAVID gene enrichment analysis were performed to identify dysregulated candidate genes compared to control databases. Immunohistochemistry was used to detect the protein expression of and in CT-pNEN specimens.

RESULTS

Mutated genes known in the literature in pNENs like (35% of cases), (18-20% of cases) and (1.4% of cases) were identified in cases of CT-pNENs. New somatic SNVs in , and have not been described in CT- pNENs, yet. Pathogenic germline mutations in and were found in three of five cases. Mutations of (calcitonin) and the corresponding receptor were found in all five tumor samples, but none of them resulted in protein sequelae or clinical relevance. All five tumor cases showed single nucleotide variations (SNVs) in , and four cases showed SNVs in , both of which were membrane-bound mucins. Immunohistochemistry showed protein expression of in two cases and in one case, and the liver metastasis of a third case was double positive for and . The homologous recombination deficiency (HRD) score of all tumors was low.

DISCUSSION

CT-pNENs have a unique molecular signature compared to other pNEN subtypes, specifically involving the and the family genes. However, a major limitation of our study was the relative small number of only five cases. Therefore, our WES data should be interpreted with caution and the mutation landscape in CT-pNENs needs to be verified by a larger number of patients. Further research is needed to explain differences in pathogenesis compared with other pNENs. In particular, multi-omics data such as RNASeq, methylation and whole genome sequencing could be informative.