Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system

Abstract

ObjectiveInsulinomas and non-functional pancreatic neuroendocrine tumours (NF-PanNETs) have distinctive clinical presentations but share similar pathological features. Their genetic bases have not been comprehensively compared. Herein, we used whole-genome/whole-exome sequencing (WGS/WES) to identify genetic differences between insulinomas and NF-PanNETs.DesignThe mutational profiles and copy-number variation (CNV) patterns of 211 PanNETs, including 84 insulinomas and 127 NF-PanNETs, were obtained from WGS/WES data provided by Peking Union Medical College Hospital and the International Cancer Genome Consortium. Insulinoma RNA sequencing and immunohistochemistry data were assayed.ResultsPanNETs were categorised based on CNV patterns: amplification, copy neutral and deletion. Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. In contrast, NF-PanNETs had all three CNV patterns, and NF-PanNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes. NF-PanNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period.ConclusionThese WGS/WES data allowed a comprehensive assessment of genetic differences between insulinomas and NF-PanNETs, reclassifying these tumours into novel molecular subtypes. We also proposed a novel relapse risk stratification system using CNV patterns and DAXX/ATRX mutations.

Long noncoding RNA‐mRNA expression profiles and validation in pancreatic neuroendocrine neoplasms

“…12 Nonfunctional pNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2-year period. 12 Long noncoding RNA (lncRNA) plays an important role in tumour development. LncRNA may affect the occurrence and development of tumours through protein modification, chromosome reconstruction, promotion or inhibition of target gene expression, intervention of transcriptional regulatory factors, epigenetic modification and other unknown ways.…”

“…CNV‐neutral insulinomas exhibited an elevated rate of YY1 mutations . In contrast, nonfunctional pNENs had all three CNV patterns, and nonfunctional pNETs with CNV deletions had a high rate of loss‐of‐function mutations of tumour suppressor genes . Nonfunctional pNETs with CNV alterations (amplification and deletion) had an elevated risk of relapse, and additional DAXX/ATRX mutations could predict an increased relapse risk in the first 2‐year period …”

“…Another whole‐genome/whole‐exome sequencing (WGS/WES) analysis of 84 insulinomas and 127 nonfunctional pNENs revealed that pNENs were categorized based on CNV patterns: amplification, copy neutral and deletion . Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions . CNV‐neutral insulinomas exhibited an elevated rate of YY1 mutations .…”

“…12 Insulinomas had CNV amplifications and copy neutral and lacked CNV deletions. 12 CNV-neutral insulinomas exhibited an elevated rate of YY1 mutations. 12 In contrast, nonfunctional pNENs had all three CNV patterns, and nonfunctional pNETs with CNV deletions had a high rate of loss-of-function mutations of tumour suppressor genes.…”

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

“…In addition to driver mutations affecting individual genes, copy number aberrations (CNA) have been used to characterize these tumors 16,[24][25][26] . Recent work has revealed four distinct subtypes based on chromosome arm length CNA patterns: i) recurring copy number losses of specific chromosomes, ii) limited copy number events with mostly loss of chromosome 11, iii) polyploidy tumors and iv) aneuploidy tumors 16 .…”