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

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Whole-genome and Transcriptome Sequencing of Prostate Cancer Identify New Genetic Alterations Driving Disease Progression.
European Urology ( IF 23.4 ) Pub Date : 2017-09-18 , DOI: 10.1016/j.eururo.2017.08.027
Shancheng Ren ₁ , Gong-Hong Wei ₂ , Dongbing Liu ₃ , Liguo Wang ₄ , Yong Hou ₅ , Shida Zhu ₆ , Lihua Peng ₇ , Qin Zhang ₂ , Yanbing Cheng ₈ , Hong Su ₃ , Xiuqing Zhou ₃ , Jibin Zhang ₉ , Fuqiang Li ₃ , Hancheng Zheng ₉ , Zhikun Zhao ₁₀ , Changjun Yin ₁₁ , Zengquan He ₉ , Xin Gao ₁₂ , Haiyen E Zhau ₁₃ , Chia-Yi Chu ₁₃ , Jason Boyang Wu ₁₃ , Colin Collins ₁₄ , Stanislav V Volik ₁₄ , Robert Bell ₁₄ , Jiaoti Huang ₁₅ , Kui Wu ₃ , Danfeng Xu ₁₆ , Dingwei Ye ₁₇ , Yongwei Yu ₁₈ , Lianhui Zhu ₁ , Meng Qiao ₁ , Hang-Mao Lee ₂ , Yuehong Yang ₂ , Yasheng Zhu ₁ , Xiaolei Shi ₁ , Rui Chen ₁ , Yang Wang ₁₈ , Weidong Xu ₁ , Yanqiong Cheng ₁ , Chuanliang Xu ₁ , Xu Gao ₁ , Tie Zhou ₁ , Bo Yang ₁ , Jianguo Hou ₁ , Li Liu ₉ , Zhensheng Zhang ₁ , Yao Zhu ₁₇ , Chao Qin ₁₁ , Pengfei Shao ₁₁ , Jun Pang ₁₂ , Leland W K Chung ₁₃ , Jianfeng Xu ₁₉ , Chin-Lee Wu ₂₀ , Weide Zhong ₂₁ , Xun Xu ₃ , Yingrui Li ₉ , Xiuqing Zhang ₉ , Jian Wang ₂₂ , Huanming Yang ₂₂ , Jun Wang ₂₃ , Haojie Huang ₂₄ , Yinghao Sun ₁

Affiliation

Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.
BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China.
Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, USA.
BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; Division of Genomics and Bioinformatics, CUHK-BGI Innovation Institute of Trans-Omics, The Chinese University of Hong Kong, Hong Kong, China.
BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; BGI Education Center, University of Chinese Academy of Sciences, Shenzhen, China.
BGI-Shenzhen, Shenzhen, China; Division of Genomics and Bioinformatics, CUHK-BGI Innovation Institute of Trans-Omics, The Chinese University of Hong Kong, Hong Kong, China.
BGI-Shenzhen, Shenzhen, China.
BGI-Shenzhen, Shenzhen, China; China National GeneBank-Shenzhen, BGI-Shenzhen, Shenzhen, China; School of Biological Science and Medical Engineering, Southeast University, Nanjing, China; State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China.
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Uro-Oncology Research Program, Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Pathology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China; Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA.
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China.
BGI-Shenzhen, Shenzhen, China; James D. Watson Institute of Genome Sciences, Hangzhou, China.
BGI-Shenzhen, Shenzhen, China; Department of Biology, University of Copenhagen, Copenhagen, Denmark; The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA.

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.

更新日期：2017-09-18

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