Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort

Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas, and the current histopathological classifications are of limited use in clinical decision-making. There is an unmet need to identify new biomarkers for prognosis-informative molecular subtyping and ultimately for prec...

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Autores principales:	Qian Zhan, Chenlei Wen, Yi Zhao, Lu Fang, Yangbing Jin, Zehui Zhang, Siyi Zou, Fanlu Li, Ying Yang, Lijia Wu, Jiabin Jin, Xiongxiong Lu, Junjie Xie, Dongfeng Cheng, Zhiwei Xu, Jun Zhang, Jiancheng Wang, XiaXing Deng, Hao Chen, Chenghong Peng, Hongwei Li, Henghui Zhang, Hai Fang, Chaofu Wang, Baiyong Shen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Pancreatic adenocarcinoma Molecular subtyping Copy number variations DNA repair Receptor tyrosine kinase signaling Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/8368ecf9a37246a68cf63c55ab565e34
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spelling	oai:doaj.org-article:8368ecf9a37246a68cf63c55ab565e342021-11-26T04:31:45ZIdentification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort2352-396410.1016/j.ebiom.2021.103716https://doaj.org/article/8368ecf9a37246a68cf63c55ab565e342021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421005107https://doaj.org/toc/2352-3964Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas, and the current histopathological classifications are of limited use in clinical decision-making. There is an unmet need to identify new biomarkers for prognosis-informative molecular subtyping and ultimately for precision medicine. Methods: We profiled genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNV). Using the CNV information, we performed unsupervised consensus clustering of these patients, differential CNV analysis and functional/pathway enrichment analysis. Cox regression was conducted for progression-free survival analysis, the elastic net algorithm used for prognostic model construction, and rank-based gene set enrichment analysis for exploring tumor microenvironments. Findings: Our data did not support prognostic value of point mutations in either highly mutated genes (such as KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair genes. Instead, associated with worse prognosis were amplified genes involved in DNA repair and receptor tyrosine kinase (RTK) related signalings. Motivated by this observation, we categorized patients into four molecular subtypes (namely repair-deficient, proliferation-active, repair-proficient and repair-enhanced) that differed in prognosis, and also constructed a prognostic model that can stratify patients with low or high risk of relapse. Finally, we analyzed publicly available datasets, not only reinforcing the prognostic value of our identified genes in DNA repair and RTK related signalings, but also identifying tumor microenvironment correlates with prognostic risks. Interpretation: Together with the evidence from genomic footprint analysis, we suggest that repair-deficient and proliferation-active subtypes are better suited for DNA damage therapies, while immunotherapy is highly recommended for repair-proficient and repair-enhanced subtypes. Our results represent a significant step in molecular subtyping, diagnosis and management for PAAD patients. Funding: This work was supported by the National Natural Science Foundation of China (grant numbers 81470894, 81502695, 81672325, 81871906, 82073326, 82103482 and 32170663), the Shanghai Sailing Program (grant number 20YF1426900), and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (awarded to H.F.).Qian ZhanChenlei WenYi ZhaoLu FangYangbing JinZehui ZhangSiyi ZouFanlu LiYing YangLijia WuJiabin JinXiongxiong LuJunjie XieDongfeng ChengZhiwei XuJun ZhangJiancheng WangXiaXing DengHao ChenChenghong PengHongwei LiHenghui ZhangHai FangChaofu WangBaiyong ShenElsevierarticlePancreatic adenocarcinomaMolecular subtypingCopy number variationsDNA repairReceptor tyrosine kinase signalingMedicineRMedicine (General)R5-920ENEBioMedicine, Vol 74, Iss , Pp 103716- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pancreatic adenocarcinoma Molecular subtyping Copy number variations DNA repair Receptor tyrosine kinase signaling Medicine R Medicine (General) R5-920
spellingShingle	Pancreatic adenocarcinoma Molecular subtyping Copy number variations DNA repair Receptor tyrosine kinase signaling Medicine R Medicine (General) R5-920 Qian Zhan Chenlei Wen Yi Zhao Lu Fang Yangbing Jin Zehui Zhang Siyi Zou Fanlu Li Ying Yang Lijia Wu Jiabin Jin Xiongxiong Lu Junjie Xie Dongfeng Cheng Zhiwei Xu Jun Zhang Jiancheng Wang XiaXing Deng Hao Chen Chenghong Peng Hongwei Li Henghui Zhang Hai Fang Chaofu Wang Baiyong Shen Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
description	Background: Pancreatic adenocarcinoma (PAAD) is one of the most lethal carcinomas, and the current histopathological classifications are of limited use in clinical decision-making. There is an unmet need to identify new biomarkers for prognosis-informative molecular subtyping and ultimately for precision medicine. Methods: We profiled genomic alterations for 608 PAAD patients in a Chinese cohort, including somatic mutations, pathogenic germline variants and copy number variations (CNV). Using the CNV information, we performed unsupervised consensus clustering of these patients, differential CNV analysis and functional/pathway enrichment analysis. Cox regression was conducted for progression-free survival analysis, the elastic net algorithm used for prognostic model construction, and rank-based gene set enrichment analysis for exploring tumor microenvironments. Findings: Our data did not support prognostic value of point mutations in either highly mutated genes (such as KRAS, TP53, CDKN2A and SMAD4) or homologous recombination repair genes. Instead, associated with worse prognosis were amplified genes involved in DNA repair and receptor tyrosine kinase (RTK) related signalings. Motivated by this observation, we categorized patients into four molecular subtypes (namely repair-deficient, proliferation-active, repair-proficient and repair-enhanced) that differed in prognosis, and also constructed a prognostic model that can stratify patients with low or high risk of relapse. Finally, we analyzed publicly available datasets, not only reinforcing the prognostic value of our identified genes in DNA repair and RTK related signalings, but also identifying tumor microenvironment correlates with prognostic risks. Interpretation: Together with the evidence from genomic footprint analysis, we suggest that repair-deficient and proliferation-active subtypes are better suited for DNA damage therapies, while immunotherapy is highly recommended for repair-proficient and repair-enhanced subtypes. Our results represent a significant step in molecular subtyping, diagnosis and management for PAAD patients. Funding: This work was supported by the National Natural Science Foundation of China (grant numbers 81470894, 81502695, 81672325, 81871906, 82073326, 82103482 and 32170663), the Shanghai Sailing Program (grant number 20YF1426900), and the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (awarded to H.F.).
format	article
author	Qian Zhan Chenlei Wen Yi Zhao Lu Fang Yangbing Jin Zehui Zhang Siyi Zou Fanlu Li Ying Yang Lijia Wu Jiabin Jin Xiongxiong Lu Junjie Xie Dongfeng Cheng Zhiwei Xu Jun Zhang Jiancheng Wang XiaXing Deng Hao Chen Chenghong Peng Hongwei Li Henghui Zhang Hai Fang Chaofu Wang Baiyong Shen
author_facet	Qian Zhan Chenlei Wen Yi Zhao Lu Fang Yangbing Jin Zehui Zhang Siyi Zou Fanlu Li Ying Yang Lijia Wu Jiabin Jin Xiongxiong Lu Junjie Xie Dongfeng Cheng Zhiwei Xu Jun Zhang Jiancheng Wang XiaXing Deng Hao Chen Chenghong Peng Hongwei Li Henghui Zhang Hai Fang Chaofu Wang Baiyong Shen
author_sort	Qian Zhan
title	Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
title_short	Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
title_full	Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
title_fullStr	Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
title_full_unstemmed	Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort
title_sort	identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a chinese cohort
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8368ecf9a37246a68cf63c55ab565e34
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Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort

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