Integrated genomic and molecular characterization of cervical cancer

作者：Robert D. Burk, Zigui Chen, Saller Cf, Katherine Tarvin, André L. Carvalho, Cristovam Scapulatempo-Neto, Henrique C. Silveira, José H. Fregnani, Chad J. Creighton, Matthew L. Anderson, Patricia Castro, Sophia S. Wang, C Yau, Christopher Benz, A. Gordon Robertson, Karen Mungall, Lynette Lim, Reanne Bowlby, Sara Sadeghi, Denise Brooks, Payal Sipahimalani, Richard Mar, Ally Ai, Amanda Clarke, Andrew J. Mungall, Angela Tam, Darlene Lee, Eric Chuah, Jacqueline E. Schein, Kane Tse, Katayoon Kasaian, Yussanne Ma, Marco A. Marra, Michael Mayo, Miruna Balasundaram, Nina Thiessen, Noreen Dhalla, Rebecca Carlsen, Richard A. Moore, Robert A. Holt, Steven J.M. Jones, Tina Wong, Angeliki Pantazi, Michael Parfenov, Raju Kucherlapati, Angela Hadjipanayis, J G Seidman, Melanie Kucherlapati, Xiaojia Ren, Andrew W. Xu, Lixing Yang, Peter J. Park, So Lee, Brenda Rabeno, Lori Huelsenbeck-Dill, Mark Borowsky, Mark Cadungog, Mary Iacocca, Nicholas Petrelli, Patricia Swanson, Akinyemi I. Ojesina, Bradley A. Murray, Hailei Zhang, Andrew D. Cherniack, Carrie Sougnez, Chandra Sekhar Pedamallu, Lee Lichtenstein, M. Meyerson, Michael S. Noble, David I. Heiman, Doug Voet, Getz Gs, Gordon Saksena, Jaegil Kim, Juliann Shih, Juok Cho, Michael S. Lawrence, Nils Gehlenborg, Pei Lin, Rameen Beroukhim, Scott Frazer, Stacey B. Gabriel, Steven E. Schumacher, Xuan Le, George Sandusky, Sally N. Adebamowo, Teniola Akeredolu, Clement Adebamowo, Sheila M. Reynolds, Ilya Shmulevich, Candace Shelton, Daniel Crain, David Mallery, Erin Curley, Johanna Gardner, Robert Penny, Scott Morris, Troy Shelton, J B Liu, Laxmi Lolla, Sudha Chudamani, Ye Wu, Michael Birrer, Michael D. McLellan, Matthew H. Bailey, Christopher A. Miller, Matthew A. Wyczalkowski, Robert S. Fulton, Catrina C. Fronick, Charles Lu, Elaine R. Mardis, Elizabeth L. Appelbaum, Heather K. Schmidt, Lucinda A. Fulton, Matthew G. Cordes, Tiandao Li, Li Ding, Richard K. Wilson, Janet S. Rader, Behnaz Behmaram, Denise Uyar, William Bradley, John Wrangle, Alessandro Pastore, Douglas A. Levine, Fanny Dao, Jianjiong Gao, Nikolaus Schultz, Chris Sander, Marc Ladanyi, Mark Einstein, Teeter Rr, S Benz, Nicolas Wentzensen, Ina Felau, Jean C. Zenklusen, Clara Bodelón, John A. Demchok, Liming Yang, Margi Sheth, Martin L. Ferguson, Roy W. Tarnuzzer, Yang Hp, MH Schiffman, Jiashan Zhang, Zhining Wang, Tanja Davidsen, Olayinka Olaniyan, Carolyn M. Hutter, Heidi J. Sofia, Dmitry A. Gordenin, Kin Chan, Steven A. Roberts, Leszek J. Klimczak, Waes Cv, Zhong Chen, Anthony D. Saleh, H Cheng, Jeremy Parfitt, John Bartlett, Monique Albert, Angel Arnaout, Harman Sekhon, Sébastien Gilbert, Myron Peto, Jerome Myers, J R Harr, John Eckman, Julie Bergsten, Kelinda Tucker, Leigh Anne Zach, Karlan By, Jenny Lester, Sandra Oršulić, Qiang Sun, Rashi Naresh, T Pihl, Yunhu Wan, Howard Zaren, Jennifer Sapp, Judy Miller, Paul Drwiega, Kristen Leraas, Tara M. Lichtenberg, Erik Zmuda, Jay Bowen, Jessica Frick, Julie M. Gastier-Foster, Lisa Wise, Mark Gerken, Nilsa C. Ramirez, Ludmila Danilova, Leslie Cope, Baylin Sb, Helga B. Salvesen, Christopher P. Vellano, Zhenlin Ju, Lixia Diao, Hongyun Zhao, Zechen Chong, Michaël Ryan, Emmanuel Martínez-Ledesma, Roeland G. Verhaak, Lauren Averett Byers, Yuan Yuan, Ken Chen, Shiyun Ling, G B Mills, Yiling Lu, Rehan Akbani, Sahil Seth, Han Liang, Yi-Xiang Wang, Leng Han, John N. Weinstein, Christopher A. Bristow, Wei Zhang, Harshad S. Mahadeshwar, Huandong Sun, Jiabin Tang, Jianhua Zhang, Xingzhi Song, Alexei Protopopov, Kenna R. Mills Shaw, Lynda Chin, Oluwole Olabode, DiSaia Pj, Amie Radenbaugh, David Haussler, Jingchun Zhu, Josh M Stuart, Prabhakar Chalise, Devin Koestler, Brooke L. Fridley, Andrew K. Godwin, Rashna Madan, Giovanni Ciriello, C Caballero Martínez, Kelly Higgins, Therese Bocklage, Auman Jt, Charles M. Perou, Donghui Tan, Joel S. Parker, Katherine A. Hoadley, Matthew D. Wilkerson, Piotr A. Mieczkowski, Tara Skelly, Umadevi Veluvolu, D Neil Hayes, Rathmell Wg, Alan P. Hoyle, Janae V. Simons, Junyuan Wu, Lisle E. Mose, Matthew G. Soloway, Saianand Balu, 孟绍武, Stuart R. Jefferys, Tom Bodenheimer, Yan Shi, Jeffrey Roach, Leigh B. Thorne, Lori Boice, Mei Huang, Corbin D. Jones, Rosemary Zuna, Joan Walker, Gunderson Ch, Carie Snowbarger, David Brown, Katherine Moxley, Kathleen Moore, Andrade Kl, Lisa Landrum, R. S. Mannel, Scott Mcmeekin, Starla Johnson, Tina Nelson, Esther Elishaev, Rajiv Dhir, Edwards Rp, Rohit Bhargava, Daniel G. Tiezzi, de Andrade Jm, Houtan Noushmehr, Carlos Gilberto Carlotti, Daniela Pretti da Cunha Tirapelli, Daniel J. Weisenberger, David J. Van Den Berg, Dennis T. Maglinte, Moiz Bootwalla, Phillip H. Lai, Timothy Triche, Elizabeth M. Swisher, Kathy Agnew, Carl Simon Shelley, P O Laird, Julie Schwarz, Grigsby Pw, David Mutch · 发表于：Nature · 年份：2017 · DOI：10.1038/nature21386 · 被引用次数：1622 · 研究领域：Cancer-related molecular mechanisms research、Cervical Cancer and HPV Research、Cancer Immunotherapy and Biomarkers

Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. This paper describes molecular subtypes of cervical cancers, including squamous cell carcinoma and adenocarcinoma clusters defined by HPV status and molecular features, and distinct molecular pathways that are activated in cervical carcinomas caused by different somatic alterations...