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Abstract
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.
- pancreas
- neuroendocrine tumours
- gene mutation
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Footnotes
XH and SQ are joint first authors.
YZ, KW and WW contributed equally.
Correction notice This article has been corrected since it published Online First. The correspondence details have been updated.
Contributors Study design: WWu, KW, YZ and DL. Study recruitment, clinical sample and data acquisition: XHo, RJ, HC, LL, HD, JJ, TZ, QL, MD, LC, XHa and DG. Bioinformatic analysis: SQ, XHo, FL, ZZ, CY, SL and KW. Statistical analysis: SQ, XHo, FL and RJ. Pathological experiment: WWa, HW, JW, CJ, XL and ZL. Primary results interpretation: XHo, SQ, RJ, LL and WWu. Manuscript drafting: XHo, SQ, RJ, JP, WWu and KW. All authors contributed to and critically reviewed the manuscript.
Funding This work was supported in part by Chinese Academy of Medical Sciences Initiative for Innovative Medicine (CAMS-I2M) 2017-I2M-1-001; National Natural Science Foundation of China (NSFC 81573009, 81773292, 81603157), PUMCH Science Fund for Junior Faculty (JQ201507, pumch-2016-2.22). Science, Technology and Innovation Commission of Shenzhen Municipality under grant no. JCYJ20160531193931852.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval Institutional Review Board of Peking Union Medical College Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.