Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

Shancheng Ren, Gong Hong Wei, Dongbing Liu, Liguo Wang, Yong Hou, Shida Zhu, Lihua Peng, Qin Zhang, Yanbing Cheng, Hong Su, Xiuqing Zhou, Jibin Zhang, Fuqiang Li, Hancheng Zheng, Zhikun Zhao, Changjun Yin, Zengquan He, Xin Gao, Haiyen E. Zhau, Chia Yi ChuJason Boyang Wu, Colin Collins, Stanislav V. Volik, Robert Bell, Jiaoti Huang, Kui Wu, Danfeng Xu, Dingwei Ye, Yongwei Yu, Lianhui Zhu, Meng Qiao, Hang Mao Lee, Yuehong Yang, Yasheng Zhu, Xiaolei Shi, Rui Chen, Yang Wang, Weidong Xu, Yanqiong Cheng, Chuanliang Xu, Xu Gao, Tie Zhou, Bo Yang, Jianguo Hou, Li Liu, Zhensheng Zhang, Yao Zhu, Chao Qin, Pengfei Shao, Jun Pang, Leland W.K. Chung, Jianfeng Xu, Chin Lee Wu, Weide Zhong, Xun Xu, Yingrui Li, Xiuqing Zhang, Jian Wang, Huanming Yang, Jun Wang, Haojie Huang, Yinghao Sun

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. We presented the first comprehensive genetic alteration landscape of prostate cancer in Chinese men and identify novel genes and progression pathways that may help advance prostate cancer diagnosis, prognosis, and personalized medicine.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Transcriptome
Disease Progression
Prostatic Neoplasms
Genome
Prostate
Neoplasms
Tumor Suppressor Genes
Genes
High-Throughput Nucleotide Sequencing
Precision Medicine
Inborn Genetic Diseases
Survival
Gene Amplification
Neoplasm Genes
Androgen Receptors
Population
Regression Analysis
Neoplasm Metastasis
Recurrence

Keywords

  • AR coactivator mutation
  • Axon guidance pathway
  • CHD1 deletion
  • Chinese prostate cancer
  • Clustered deleted tumor suppressor genes
  • Personalized medicine
  • Prognosis
  • RNA-seq
  • TMPRSS2-ERG fusion
  • Whole genome sequencing

ASJC Scopus subject areas

  • Urology

Cite this

Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression. / Ren, Shancheng; Wei, Gong Hong; Liu, Dongbing; Wang, Liguo; Hou, Yong; Zhu, Shida; Peng, Lihua; Zhang, Qin; Cheng, Yanbing; Su, Hong; Zhou, Xiuqing; Zhang, Jibin; Li, Fuqiang; Zheng, Hancheng; Zhao, Zhikun; Yin, Changjun; He, Zengquan; Gao, Xin; Zhau, Haiyen E.; Chu, Chia Yi; Wu, Jason Boyang; Collins, Colin; Volik, Stanislav V.; Bell, Robert; Huang, Jiaoti; Wu, Kui; Xu, Danfeng; Ye, Dingwei; Yu, Yongwei; Zhu, Lianhui; Qiao, Meng; Lee, Hang Mao; Yang, Yuehong; Zhu, Yasheng; Shi, Xiaolei; Chen, Rui; Wang, Yang; Xu, Weidong; Cheng, Yanqiong; Xu, Chuanliang; Gao, Xu; Zhou, Tie; Yang, Bo; Hou, Jianguo; Liu, Li; Zhang, Zhensheng; Zhu, Yao; Qin, Chao; Shao, Pengfei; Pang, Jun; Chung, Leland W.K.; Xu, Jianfeng; Wu, Chin Lee; Zhong, Weide; Xu, Xun; Li, Yingrui; Zhang, Xiuqing; Wang, Jian; Yang, Huanming; Wang, Jun; Huang, Haojie; Sun, Yinghao.

In: European Urology, 01.01.2017.

Research output: Contribution to journalArticle

Ren, S, Wei, GH, Liu, D, Wang, L, Hou, Y, Zhu, S, Peng, L, Zhang, Q, Cheng, Y, Su, H, Zhou, X, Zhang, J, Li, F, Zheng, H, Zhao, Z, Yin, C, He, Z, Gao, X, Zhau, HE, Chu, CY, Wu, JB, Collins, C, Volik, SV, Bell, R, Huang, J, Wu, K, Xu, D, Ye, D, Yu, Y, Zhu, L, Qiao, M, Lee, HM, Yang, Y, Zhu, Y, Shi, X, Chen, R, Wang, Y, Xu, W, Cheng, Y, Xu, C, Gao, X, Zhou, T, Yang, B, Hou, J, Liu, L, Zhang, Z, Zhu, Y, Qin, C, Shao, P, Pang, J, Chung, LWK, Xu, J, Wu, CL, Zhong, W, Xu, X, Li, Y, Zhang, X, Wang, J, Yang, H, Wang, J, Huang, H & Sun, Y 2017, 'Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression', European Urology. https://doi.org/10.1016/j.eururo.2017.08.027
Ren, Shancheng ; Wei, Gong Hong ; Liu, Dongbing ; Wang, Liguo ; Hou, Yong ; Zhu, Shida ; Peng, Lihua ; Zhang, Qin ; Cheng, Yanbing ; Su, Hong ; Zhou, Xiuqing ; Zhang, Jibin ; Li, Fuqiang ; Zheng, Hancheng ; Zhao, Zhikun ; Yin, Changjun ; He, Zengquan ; Gao, Xin ; Zhau, Haiyen E. ; Chu, Chia Yi ; Wu, Jason Boyang ; Collins, Colin ; Volik, Stanislav V. ; Bell, Robert ; Huang, Jiaoti ; Wu, Kui ; Xu, Danfeng ; Ye, Dingwei ; Yu, Yongwei ; Zhu, Lianhui ; Qiao, Meng ; Lee, Hang Mao ; Yang, Yuehong ; Zhu, Yasheng ; Shi, Xiaolei ; Chen, Rui ; Wang, Yang ; Xu, Weidong ; Cheng, Yanqiong ; Xu, Chuanliang ; Gao, Xu ; Zhou, Tie ; Yang, Bo ; Hou, Jianguo ; Liu, Li ; Zhang, Zhensheng ; Zhu, Yao ; Qin, Chao ; Shao, Pengfei ; Pang, Jun ; Chung, Leland W.K. ; Xu, Jianfeng ; Wu, Chin Lee ; Zhong, Weide ; Xu, Xun ; Li, Yingrui ; Zhang, Xiuqing ; Wang, Jian ; Yang, Huanming ; Wang, Jun ; Huang, Haojie ; Sun, Yinghao. / Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression. In: European Urology. 2017.
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title = "Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression",
abstract = "Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23{\%} of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17{\%} of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. We presented the first comprehensive genetic alteration landscape of prostate cancer in Chinese men and identify novel genes and progression pathways that may help advance prostate cancer diagnosis, prognosis, and personalized medicine.",
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author = "Shancheng Ren and Wei, {Gong Hong} and Dongbing Liu and Liguo Wang and Yong Hou and Shida Zhu and Lihua Peng and Qin Zhang and Yanbing Cheng and Hong Su and Xiuqing Zhou and Jibin Zhang and Fuqiang Li and Hancheng Zheng and Zhikun Zhao and Changjun Yin and Zengquan He and Xin Gao and Zhau, {Haiyen E.} and Chu, {Chia Yi} and Wu, {Jason Boyang} and Colin Collins and Volik, {Stanislav V.} and Robert Bell and Jiaoti Huang and Kui Wu and Danfeng Xu and Dingwei Ye and Yongwei Yu and Lianhui Zhu and Meng Qiao and Lee, {Hang Mao} and Yuehong Yang and Yasheng Zhu and Xiaolei Shi and Rui Chen and Yang Wang and Weidong Xu and Yanqiong Cheng and Chuanliang Xu and Xu Gao and Tie Zhou and Bo Yang and Jianguo Hou and Li Liu and Zhensheng Zhang and Yao Zhu and Chao Qin and Pengfei Shao and Jun Pang and Chung, {Leland W.K.} and Jianfeng Xu and Wu, {Chin Lee} and Weide Zhong and Xun Xu and Yingrui Li and Xiuqing Zhang and Jian Wang and Huanming Yang and Jun Wang and Haojie Huang and Yinghao Sun",
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TY - JOUR

T1 - Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression

AU - Ren, Shancheng

AU - Wei, Gong Hong

AU - Liu, Dongbing

AU - Wang, Liguo

AU - Hou, Yong

AU - Zhu, Shida

AU - Peng, Lihua

AU - Zhang, Qin

AU - Cheng, Yanbing

AU - Su, Hong

AU - Zhou, Xiuqing

AU - Zhang, Jibin

AU - Li, Fuqiang

AU - Zheng, Hancheng

AU - Zhao, Zhikun

AU - Yin, Changjun

AU - He, Zengquan

AU - Gao, Xin

AU - Zhau, Haiyen E.

AU - Chu, Chia Yi

AU - Wu, Jason Boyang

AU - Collins, Colin

AU - Volik, Stanislav V.

AU - Bell, Robert

AU - Huang, Jiaoti

AU - Wu, Kui

AU - Xu, Danfeng

AU - Ye, Dingwei

AU - Yu, Yongwei

AU - Zhu, Lianhui

AU - Qiao, Meng

AU - Lee, Hang Mao

AU - Yang, Yuehong

AU - Zhu, Yasheng

AU - Shi, Xiaolei

AU - Chen, Rui

AU - Wang, Yang

AU - Xu, Weidong

AU - Cheng, Yanqiong

AU - Xu, Chuanliang

AU - Gao, Xu

AU - Zhou, Tie

AU - Yang, Bo

AU - Hou, Jianguo

AU - Liu, Li

AU - Zhang, Zhensheng

AU - Zhu, Yao

AU - Qin, Chao

AU - Shao, Pengfei

AU - Pang, Jun

AU - Chung, Leland W.K.

AU - Xu, Jianfeng

AU - Wu, Chin Lee

AU - Zhong, Weide

AU - Xu, Xun

AU - Li, Yingrui

AU - Zhang, Xiuqing

AU - Wang, Jian

AU - Yang, Huanming

AU - Wang, Jun

AU - Huang, Haojie

AU - Sun, Yinghao

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. We presented the first comprehensive genetic alteration landscape of prostate cancer in Chinese men and identify novel genes and progression pathways that may help advance prostate cancer diagnosis, prognosis, and personalized medicine.

AB - Background: Global disparities in prostate cancer (PCa) incidence highlight the urgent need to identify genomic abnormalities in prostate tumors in different ethnic populations including Asian men. Objective: To systematically explore the genomic complexity and define disease-driven genetic alterations in PCa. Design, setting, and participants: The study sequenced whole-genome and transcriptome of tumor-benign paired tissues from 65 treatment-naive Chinese PCa patients. Subsequent targeted deep sequencing of 293 PCa-relevant genes was performed in another cohort of 145 prostate tumors. Outcome measurements and statistical analysis: The genomic alteration landscape in PCa was analyzed using an integrated computational pipeline. Relationships with PCa progression and survival were analyzed using nonparametric test, log-rank, and multivariable Cox regression analyses. Results and limitations: We demonstrated an association of high frequency of CHD1 deletion with a low rate of TMPRSS2-ERG fusion and relatively high percentage of mutations in androgen receptor upstream activator genes in Chinese patients. We identified five putative clustered deleted tumor suppressor genes and provided experimental and clinical evidence that PCDH9, deleted/loss in approximately 23% of tumors, functions as a novel tumor suppressor gene with prognostic potential in PCa. Furthermore, axon guidance pathway genes were frequently deregulated, including gain/amplification of PLXNA1 gene in approximately 17% of tumors. Functional and clinical data analyses showed that increased expression of PLXNA1 promoted prostate tumor growth and independently predicted prostate tumor biochemical recurrence, metastasis, and poor survival in multi-institutional cohorts of patients with PCa. A limitation of this study is that other genetic alterations were not experimentally investigated. Conclusions: There are shared and salient genetic characteristics of PCa in Chinese and Caucasian men. Novel genetic alterations in PCDH9 and PLXNA1 were associated with disease progression. Patient summary: We reported the first large-scale and comprehensive genomic data of prostate cancer from Asian population. Identification of these genetic alterations may help advance prostate cancer diagnosis, prognosis, and treatment. We presented the first comprehensive genetic alteration landscape of prostate cancer in Chinese men and identify novel genes and progression pathways that may help advance prostate cancer diagnosis, prognosis, and personalized medicine.

KW - AR coactivator mutation

KW - Axon guidance pathway

KW - CHD1 deletion

KW - Chinese prostate cancer

KW - Clustered deleted tumor suppressor genes

KW - Personalized medicine

KW - Prognosis

KW - RNA-seq

KW - TMPRSS2-ERG fusion

KW - Whole genome sequencing

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JO - European Urology

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SN - 0302-2838

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