Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas

Jiwon Koh, Soo Kyung Nam, Yoonjin Kwak, Gilhyang Kim, Ka Kyung Kim, Byung Chul Lee, Sang Hoon Ahn, Do Joong Park, Hyung Ho Kim, Kyoung Un Park, Woo Ho Kim, Hye Seung Lee

Research output: Contribution to journalArticlepeer-review

Abstract

We aimed to determine the pathogenesis of gastric mixed adenoneuroendocrine carcinoma (MANEC) and pure neuroendocrine carcinoma (NEC), which is largely unknown. Targeted DNA sequencing was performed on 34 tumor samples from 21 patients – 13 adenocarcinoma (ADC)/NEC components from MANECs and eight pure NECs – and 21 matched non-neoplastic gastric tissues. Mutational profiles of MANECs/NECs were compared with those of other tumors using public databases. The majority (64.1%; 59/92) of mutations in MANEC were shared by both ADC and NEC components. TP53 was the most commonly mutated gene in MANEC (69.2%, 9/13) and pure NEC (87.5%, 8/9). All TP53 mutations in MANEC were pathogenic mutations and were shared by both ADC and NEC components. A subset of TP53WT MANECs had a microsatellite-unstable phenotype or amplifications in various oncogenes including ERBB2 and NMYC, and the only TP53WT pure NEC harbored MYC amplification. Compared to NEC in other organs, NECs arising from the stomach had unique features including less frequent RB1 mutations. Differentially altered genes of MANEC ADC components were significantly associated with receptor tyrosine kinase signaling pathways, while differentially altered genes of MANEC NEC components were significantly associated with the NOTCH signaling pathway. Our data provide evidence suggesting a possible clonal origin of ADC and NEC components of MANEC, and we found that gastric MANECs and pure NECs are distinct entities with unique mutational profiles and underlying protein networks.

Original languageEnglish
Pages (from-to)94-105
Number of pages12
JournalJournal of Pathology
Volume253
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • gastric cancer
  • genetics
  • neuroendocrine carcinoma
  • targeted sequencing

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