Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3

Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.