Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas

Abstract

Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.

Clinicopathological features and outcome for neuroendocrine neoplasms of gastroesophageal junction: A population‐based study

“…Compared with the adenocarcinoma, NEC was more aggressive with poorly differentiated morphology . Shia et al reported the absence of an associated adenocarcinoma component was predictive of a worse outcome; however, previous studies about gastric or colorectal MANEC reported that there was no statistically significant difference in survival between MANECs and NEC . In our cohort, a number of GEJ‐NECs were mixed with high grade adenocarcinoma, the outcome of which was better than pure NECs.…”

Metastatic mixed adenoneuroendocrine carcinoma of the liver successfully resected by hepatic trisectionectomy following chemotherapy: A case report

“…Regarding the cellular origins of MANECs, NEC shares a genetic profile with conventional colorectal adenocarcinoma. Hence, these components appear to be derived from the same cellular origin as amphicrine tumor, that is, most likely pluripotent epithelial stem cells or an adenocarcinoma precursor cells that are triggered by selective cytokines in the tumor environment or by somatic mutations . Therefore, MANECs may respond to chemotherapeutic agents that target colorectal adenocarcinoma .…”

Leucine‐rich repeat‐containing G‐protein‐coupled receptor 5 expression and clinicopathological features of colorectal neuroendocrine neoplasms

“…previously reported that many NEC cases showed nuclear beta‐catenin expression . Many NEC cases harbor mutant APC; mutant APC is unable to fully target beta‐catenin for degradation and the residual beta‐catenin can still relocate to the nucleus, where it can bind TCF and activate WNT target genes . Because LGR5 is a WNT target gene, LGR5 expression might be affected by beta‐catenin expression in neuroendocrine neoplasms and especially in NEC.…”