Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system
Whole-genome sequencing reveals distinct genetic bases for insulinomas and non-functional pancreatic neuroendocrine tumours: leading to a new classification system
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全基因组测序揭示了胰岛素瘤和非功能性胰腺神经内分泌肿瘤的独特遗传基础：从而产生了新的分类系统。
DOI：
10.1136/gutjnl-2018-317233
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发表时间：
2020-05-01
期刊：
影响因子：
24.5
通讯作者：
Wu, Wenming
中科院分区：
文献类型：
--
作者：
Hong, Xiafei;Qiao, Sitan;Wu, Wenming
目的胰岛素瘤与非功能性胰腺神经内分泌肿瘤（NF-PanNETs）临床表现不同，但病理特征相似。它们的基因基础还没有被全面比较。在此，我们使用全基因组/全外显子组测序（WGS/WES）来鉴定胰岛素瘤和NF-PanNET之间的遗传差异。设计211个PanNET（包括84个胰岛素瘤和127个NF-PanNET）的突变谱和拷贝数变异（CNV）模式来自北京协和医院和国际癌症基因组联盟提供的WGS/WES数据。结果根据CNV模式将PanNET分为扩增型、拷贝中性型和缺失型。胰岛素瘤具有CNV扩增和拷贝中性，并且缺乏CNV缺失。CNV-中性胰岛素瘤表现出YY 1突变率升高。相比之下，NF-PanNET具有所有三种CNV模式，并且具有CNV缺失的NF-PanNET具有高的肿瘤抑制基因功能丧失突变率。NF-PanNETs与CNV的改变（扩增和缺失）复发的风险升高，和额外的DAXX/ATRX突变可以预测在第一个2-year periods.Conclusion复发风险增加这些WGS/WES数据允许胰岛素瘤和NF-PanNETs之间的遗传差异进行全面评估，重新分类这些肿瘤到新的分子亚型。我们还提出了一种新的复发风险分层系统，使用CNV模式和DAXX/ATRX突变。
Objective Insulinomas 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.Design The 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.Results PanNETs 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.Conclusion These 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.