Genomic dissection of gastrointestinal and lung neuroendocrine neoplasm.

Haixing Wang,Hua Bao,Lin Shen,Xiaoling Tong,Ming Lu,Xue Wu,Jie Luo,Ao Wang,Yang W Shao,Li Sun,Xiaonan Wang,Panpan Zhang

doi:10.21147/j.issn.1000-9604.2019.06.08

Abstract

ObjectiveNeuroendocrine neoplasms (NENs) are relatively rare and heterogeneous malignancies with two major subtypes: low-grade neuroendocrine tumor (NET) and high-grade neuroendocrine carcinoma (NEC). Comprehensive molecular characterization of NENs is needed to refine our understanding of the biological underpinnings of different NEN subtypes and to predict disease progression more accurately.MethodsWe performed whole-exome sequencing (WES) of NEN samples from 49 patients (25 NETs and 24 NECs) arising from the stomach, intestines or lung. Clinicopathologic features were assessed and associated with molecular events.ResultsNENs generally harbor a low mutation burden, with TP53 being the top mutated gene found in 31% of patients. Consistent with other studies, p53 signaling pathway dysfunction is significantly enriched in NECs compared to NETs (P<0.01). Other thanTP53, tissue type-specific mutation profiles of NENs were observed in our cohort compared to those reported in pancreatic NETs. Importantly, we observed significant genomic instability, with increased copy number alterations observed across the NEN genome, which was more profound in NECs and independently correlated with poor overall survival (OS) (P<0.001). NECs could be further stratified into two molecular subtypes based on OS (P<0.001) and the chromosomal instability score (CIS). Interestingly, we discovered that the gain of whole chromosome 5 occurred at the early stage of NEN development, followed by the loss of 5q exclusively in NECs (P<0.001). ConclusionsThese findings provide novel insights into the molecular characteristics of NENs and highlight the association of genomic stability with clinical outcomes.

Highlights

Neuroendocrine neoplasms (NENs) are rare, heterogeneous malignancies that are steadily rising in both prevalence and incidence [1]
Stage I−IV NENs diagnosed at different anatomical sites, including the stomach (n=29), lung (n=10) and intestines (n=10), were collectively termed NP-NENs
All lung NENs were histologically classified as small cell neuroendocrine carcinoma (NEC) in our cohort, while intestinal NENs were exclusively neuroendocrine tumor (NET) phenotypes

Summary

Introduction

Neuroendocrine neoplasms (NENs) are rare, heterogeneous malignancies that are steadily rising in both prevalence and incidence [1]. In 2010, the revised World Health Organization (WHO) classification of NENs defined three grades based on the mitotic count and Ki-67 index (G1, G2, and G3) [3]. NETs are mostly G1/G2 grade, regions of excessive proliferation comparable to G3 can be found within NETs, which is associated with reduced disease-specific survival [9]. This suggests that different molecular subtypes may exist within the same histological group, and current classification methods based on histology or the Ki-67 index may not adequately capture important differences at the molecular level

Methods

Results

Conclusion