Genetic alterations of GI‐NECs involving three main signaling pathways

Abstract

Background Gastrointestinal (GI)‐neuroendocrine neoplasms (NENs) are subclassified in neuroendocrine tumors (NETs), neuroendocrine carcinomas (NECs), and mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs). The genetic characteristics of GI‐NEN has been a hot issue in recent years, but more studies are needed to provide further details. This study aims to provide additional data about genomic characteristics of GI‐NENs and the genetic differences between NETs and NECs. Patients and Methods Thirteen samples were selected for next‐generation sequencing (NGS) analysis with a 425‐gene panel. Microsatellite instability (MSI) and tumor mutational burden (TMB) were calculated as well as immunohistochemistry (IHC) was used to test for protein expression. Results Genetic alterations were very common in NECs, but rare in NETs. The average TMB of NETs and NECs was 2.3 and 6.9, respectively. The TMB of NECs was significantly higher compared to NETs. The TP53 mutation rate was significantly higher in NECs than in NETs (100% vs. 20%), other mutations involved MTOR (n = 2, 15.4%), DDR2 (n = 3, 23.1%), ERBB4 (n = 1, 7.7%), BRCA1 (n = 1, 7.7%), BRCA2 (n = 1, 7.7%), ATM (n = 1, 7.7%), and SMAD4 (n = 1, 7.7%). Deep loss of SMAD4 (1/3, 33.3%), SDHB (1/3, 33.3%), RB1 (1/3, 33.3%), and BRCA2 (1/3, 33.3%), high‐level amplification of CRKL (1/3, 33.3%), CCNE1(1/3, 33.3%), and MCL1(1/3, 33.3%) were found in NECs. The integrated analysis found these genetic alterations frequently involve DNA repair and cell cycle, PI3K/AKT/mTOR and TGF‐β/SMAD4 signaling pathways. Conclusion Genetic alterations were very common in NECs and rare in NETs, and frequently involved three main signaling pathways. NEC patients harboring these genetic alterations may benefit from targeted therapy and PD‐1/PD‐L1 immunotherapy.

Prognostic and predictive significance of p53 and ATRX in neuroendocrine neoplasms of GIT and pancreas and their utility as an adjunct to accurate diagnosis

“…However 4 of Grade 2 NETs showed null pattern of p53 in our study. Qiong Dai et al in their study of molecular alteration in GI NENs, also found mutated pattern / Null pattern of p53 in two of G2 NETs [12]. Disease free survival among patients of Grade 2 NET with null pattern and grade 3 tumors with null pattern in our study were comparable (42 month and 32 months respectively), though one patient grade 2 NET had a higher overall survival of 114 months with disease and died of disease.…”

“…Null pattern/ mutated pattern in grade 2 NET could represent transformation of grade 2 NET to higher grade and poor survival [13]. Qiong Dai et al commented that null pattern IHC expression of p53 cannot be used to reliably distinguish NETs and NEC [12]. Like our study Qiong Dai et al found a signi cant difference in expression of p53 between NET( G2 NET, G3NET) and NEC [12].…”

“…Mutation involving p53 gene is seen is several cancers. Mutated protein accumulates into tumor cell nuclei which can be detected by immunohistochemistry [12]. Identi cation of p53 mutation facilitates grading of several tumors and plays major role in patient prognostication and treatment such as ovarian serous carcinomas [4].…”

“…Qiong Dai et al commented that null pattern IHC expression of p53 cannot be used to reliably distinguish NETs and NEC [12]. Like our study Qiong Dai et al found a signi cant difference in expression of p53 between NET( G2 NET, G3NET) and NEC [12]. Amongst high grade tumors( Ki-67 > 20%)though combined NULL pattern and mutated pattern of p53 were common among NEC compared to Grade 3 NET, the difference was not statistically signi cant possibly due to the small sample size in our study.…”