Year: 2017
Type: article
Study design: Observational Study
Abstract: 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 and HPV types. Cervical cancer is one of the main causes of cancer-related deaths worldwide, and 95% of cases result from human papilloma virus (HPV) infection. The Cancer Genome Atlas Research Network now reports the genomic and molecular characterization of 228 primary cervical cancers. The authors identify significantly mutated genes and pathways that differ by cervical cancer subtype, and find that keratin-low squamous, keratin-high squamous and adenocarcinoma-rich clusters are marked by different HPV types and molecular features.
Source: Nature
DOI: 10.1038/nature21386
Authors: Robert D. Burk, Zigui Chen, Charles Saller, Katherine Tarvin, Andre L. Carvalho, Cristovam Scapulatempo-Neto, Henrique C. Silveira, José H. Fregnani, Chad J. Creighton, Matthew L. Anderson, Patricia Castro, Sophia S. Wang, Christina Yau, Christopher Benz, A. Gordon Robertson, Karen Mungall, Lynette Lim, Reanne Bowlby, Sara Sadeghi, Denise Brooks, Payal Sipahimalani, Richard Mar, Adrian Ally, 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, Jonathan Seidman, Melanie Kucherlapati, Xiaojia Ren, Andrew W. Xu, Lixing Yang, Peter J. Park, Semin 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, Matthew Meyerson, Michael S. Noble, David I. Heiman, Doug Voet, Gad Getz, 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, Jia 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, Randall Teeter, Stephen Benz, Nicolas Wentzensen, Ina Felau, Jean C. Zenklusen, Clara Bodelon, John A. Demchok, Liming Yang, Margi Sheth, Martin L. Ferguson, Roy Tarnuzzer, Hannah Yang, Mark 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, Carter Van Waes, Zhong Chen, Anthony D. Saleh, Hui Cheng, Jeremy Parfitt, John Bartlett, Monique Albert, Angel Arnaout, Harman Sekhon, Sebastien Gilbert, Myron Peto, Jerome Myers, Jodi Harr, John Eckman, Julie Bergsten, Kelinda Tucker, Leigh Anne Zach, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Qiang Sun, Rashi Naresh, Todd Pihl, Yunhu Wan, Howard Zaren, Jennifer Sapp, Judy Miller, Paul Drwiega, Kristen M. 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, Stephen B. Baylin, Helga B. Salvesen, Christopher P. Vellano, Zhenlin Ju, Lixia Diao, Hao Zhao, Zechen Chong, Michael C. Ryan, Emmanuel Martinez-Ledesma, Roeland G. Verhaak, Lauren Averett Byers, Yuan Yuan, Ken Chen, Shiyun Ling, Gordon B. Mills, Yiling Lu, Rehan Akbani, Sahil Seth, Han Liang, Jing 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, Philip DiSaia, Amie Radenbaugh, David Haussler, Jingchun Zhu, Josh Stuart, Prabhakar Chalise, Devin Koestler, Brooke L. Fridley, Andrew K. Godwin, Rashna Madan, Giovanni Ciriello, Cathleen Martinez, Kelly Higgins, Therese Bocklage, J. Todd Auman, Charles M. Perou, Donghui Tan, Joel S. Parker, Katherine A. Hoadley, Matthew D. Wilkerson, Piotr A. Mieczkowski, Tara Skelly, Umadevi Veluvolu, D. Neil Hayes, W. Kimryn Rathmell, Alan P. Hoyle, Janae V. Simons, Junyuan Wu, Lisle E. Mose, Matthew G. Soloway, Saianand Balu, Shaowu Meng, Stuart R. Jefferys, Tom Bodenheimer, Yan Shi, Jeffrey Roach, Leigh B. Thorne, Lori Boice, Mei Huang, Corbin D. Jones, Rosemary Zuna, Joan Walker, Camille Gunderson, Carie Snowbarger, David Brown, Katherine Moxley, Kathleen Moore, Kelsi Andrade, Lisa Landrum, Robert Mannel, Scott McMeekin, Starla Johnson, Tina Nelson, Esther Elishaev, Rajiv Dhir, Robert Edwards, Rohit Bhargava, Daniel G. Tiezzi, Jurandyr M. Andrade, Houtan Noushmehr, Carlos Gilberto Carlotti Jr, Daniela Pretti da Cunha Tirapelli, Daniel J. Weisenberger, David J. Van Den Berg, Dennis T. Maglinte, Moiz S. Bootwalla, Phillip H. Lai, Timothy Triche Jr, Elizabeth M. Swisher, Kathy J. Agnew, Carl Simon Shelley, Peter W. Laird, Julie Schwarz, Perry Grigsby, David Mutch
Institutions: Albert Einstein College of Medicine, National Institute on Deafness and Other Communication Disorders, Analytical Biological Services (United States), Hospital de Câncer de Barretos, Baylor College of Medicine, City Of Hope National Medical Center, City of Hope, Beckman Research Institute, Buck Institute for Research on Aging, BC Cancer Agency, Canada's Michael Smith Genome Sciences Centre, Harvard University, National Cancer Institute, Christiana Care Health System, Broad Institute, University of Alabama at Birmingham, HudsonAlpha Institute for Biotechnology, Massachusetts Institute of Technology, Indiana University School of Medicine, Institute of Human Virology, Institute for Systems Biology, International Genomics Consortium, Massachusetts General Hospital, Washington University in St. Louis, Medical College of Wisconsin, Medical University of South Carolina, Memorial Sloan Kettering Cancer Center, Montefiore Medical Center, NantOmics LLC (United States), The University of Texas MD Anderson Cancer Center, National Hospital Abuja, National Human Genome Research Institute, National Institute of Environmental Health Sciences, London Health Sciences Centre, Ontario Institute for Cancer Research, Ottawa Hospital, Oregon Health & Science University, Penrose-St. Francis Health Services, Cedars-Sinai Medical Center, SRA International (United States), St. Joseph’s Candler Hospital, Nationwide Children's Hospital, Abigail Wexner Research Institute, Johns Hopkins University, Sidney Kimmel Comprehensive Cancer Center, University of Bergen, University of Abuja Teaching Hospital, University of California, Irvine, University of California, Santa Cruz, University of Kansas Medical Center, University of Lausanne, University of New Mexico Health Sciences Center, University of North Carolina at Chapel Hill, University of Oklahoma Health Sciences Center, University of Pittsburgh, Universidade de São Paulo, University of Southern California, University of Washington, University of Wisconsin–Madison, Van Andel Institute
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: SRA International, Massachusetts General Hospital, Massachusetts Institute of Technology, Memorial Sloan-Kettering Cancer Center, Harvard University, Nationwide Children's Hospital, Johns Hopkins University, Beckman Research Institute, City of Hope, University of South Carolina, London Health Sciences Centre, Cedars-Sinai Medical Center, Broad Institute, Canada's Michael Smith Genome Sciences Centre, Buck Institute for Research on Aging, Leidos, Hospital de Câncer de Barretos, Universitetet i Bergen, National Institutes of Health, University of Texas MD Anderson Cancer Center, School of Medicine, Indiana University, Research Institute, Nationwide Children's Hospital, Sidney Kimmel Comprehensive Cancer Center, National Human Genome Research Institute, National Cancer Institute
Awards: Large Scale Sequencing and Analysis of Genomes, The USC-JHU Cancer Epigenome Characterization Center, A Platform for Large-Scale Genomic Discovery, The BCM Tumor Genome Characterization Center, MSKCC Center for Translational Cancer Genomic Analysis, Batch effects in molecular profiling data on cancers: detection, quantitation, interpretation, and correction, UCSC-Buck Inst. Genome Data Analysis Center for TCGA Research Network (GDAC), The Human Genome Sequencing Center, Integrated analysis of protein expression data from the Reverse Phase Protein Array (RPPA) platform, Harvard Genome Characterization Center, Cancer transcriptome characterization using massively parallel DNA sequencing, Next-Generation Clustered Heat Maps for fluent, interactive exploration of omic data, Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC), The Cancer Genome Atlas Data Analysis Center, Cloud Based Resource for Data Hosting, Visualization and Analysis Using UCSC Canc, Genome Characterization Center (GCC), Gene Expression Patterns in Human Tumors Identified Using Transcript Sequencing, TCGA Data Analysis Center at Berkeley, Deep Discovery and Clinical Interpretation of Germline and Somatic Cancer Drivers, Visualization hub for genomics data exploration and translational discovery, Center for Systems Analysis of the Cancer Regulome, G8437048056, Cancer Center Support Grant
OpenAlex ID: W2575837388