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PMID: 28112728 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Integrated genomic and molecular characterization of cervical cancer.

Nature ·Vol. 543 ·No. 7645 ·2017-00-16 ·Pages 378-384

Cancer Genome Atlas Research Network, Albert Einstein College of Medicine, Analytical Biological Services, Barretos Cancer Hospital, Baylor College of Medicine, Beckman Research Institute of City of Hope, Buck Institute for Research on Aging, Canada's Michael Smith Genome Sciences Centre, Harvard Medical School, Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services, HudsonAlpha Institute for Biotechnology, ILSbio, LLC, Indiana University School of Medicine, Institute of Human Virology, Institute for Systems Biology, International Genomics Consortium, Leidos Biomedical, Massachusetts General Hospital, McDonnell Genome Institute at Washington University, Medical College of Wisconsin, Medical University of South Carolina, Memorial Sloan Kettering Cancer Center, Montefiore Medical Center, NantOmics, National Cancer Institute, National Hospital, Abuja, Nigeria, National Human Genome Research Institute, National Institute of Environmental Health Sciences, National Institute on Deafness &Other Communication Disorders, Ontario Tumour Bank, London Health Sciences Centre, Ontario Tumour Bank, Ontario Institute for Cancer Research, Ontario Tumour Bank, The Ottawa Hospital, Oregon Health &Science University, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, SRA International, St Joseph's Candler Health System, Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University, Research Institute at Nationwide Children's Hospital, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, University of Bergen, University of Texas MD Anderson Cancer Center, University of Abuja Teaching Hospital, University of Alabama at Birmingham, 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, University of São Paulo, Ribeir ão Preto Medical School, University of Southern California, University of Washington, University of Wisconsin School of Medicine &Public Health, Van Andel Research Institute, Washington University in St Louis

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.

MeSH Terms
APOBEC-1 Deaminase/genetics Adenocarcinoma/genetics B7-H1 Antigen/genetics Carcinoma, Squamous Cell/genetics Caspase 8/genetics DNA-Binding Proteins Female Genomics HLA-A Antigens/genetics Human papillomavirus 16/genetics,isolation & purification Humans Keratins/genetics Mitogen-Activated Protein Kinase Kinases/metabolism Molecular Targeted Therapy Mutation Nuclear Proteins/genetics PTEN Phosphohydrolase/genetics Phosphatidylinositol 3-Kinases/metabolism Programmed Cell Death 1 Ligand 2 Protein/genetics Protein Serine-Threonine Kinases/genetics,metabolism Proteomics Proto-Oncogene Proteins p21(ras)/genetics RNA, Long Noncoding/genetics Receptor, ErbB-3/genetics Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta/genetics,metabolism Signal Transduction Transcription Factors/genetics Uterine Cervical Neoplasms/classification,drug therapy,genetics Virus Integration
Chemicals
ARID1A protein, human B7-H1 Antigen BCAR4 non-coding RNA, human CD274 protein, human DNA-Binding Proteins HLA-A Antigens KRAS protein, human Nuclear Proteins PDCD1LG2 protein, human Programmed Cell Death 1 Ligand 2 Protein RNA, Long Noncoding Receptors, Transforming Growth Factor beta Transcription Factors Keratins ERBB3 protein, human Receptor, ErbB-3 Protein Serine-Threonine Kinases Receptor, Transforming Growth Factor-beta Type II Mitogen-Activated Protein Kinase Kinases PTEN Phosphohydrolase PTEN protein, human CASP8 protein, human Caspase 8 APOBEC-1 Deaminase Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
57 authors, click to expand affiliations / ORCID
Cancer Genome Atlas Research Network
Albert Einstein College of Medicine
Analytical Biological Services
Barretos Cancer Hospital
Baylor College of Medicine
Beckman Research Institute of City of Hope
Buck Institute for Research on Aging
Canada's Michael Smith Genome Sciences Centre
Harvard Medical School
Helen F. Graham Cancer Center &Research Institute at Christiana Care Health Services
HudsonAlpha Institute for Biotechnology
ILSbio, LLC
Indiana University School of Medicine
Institute of Human Virology
Institute for Systems Biology
International Genomics Consortium
Leidos Biomedical
Massachusetts General Hospital
McDonnell Genome Institute at Washington University
Medical College of Wisconsin
Medical University of South Carolina
Memorial Sloan Kettering Cancer Center
Montefiore Medical Center
NantOmics
National Cancer Institute
National Hospital, Abuja, Nigeria
National Human Genome Research Institute
National Institute of Environmental Health Sciences
National Institute on Deafness &Other Communication Disorders
Ontario Tumour Bank, London Health Sciences Centre
Ontario Tumour Bank, Ontario Institute for Cancer Research
Ontario Tumour Bank, The Ottawa Hospital
Oregon Health &Science University
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center
SRA International
St Joseph's Candler Health System
Eli &Edythe L. Broad Institute of Massachusetts Institute of Technology &Harvard University
Research Institute at Nationwide Children's Hospital
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
University of Bergen
University of Texas MD Anderson Cancer Center
University of Abuja Teaching Hospital
University of Alabama at Birmingham
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
University of São Paulo, Ribeir ão Preto Medical School
University of Southern California
University of Washington
University of Wisconsin School of Medicine &Public Health
Van Andel Research Institute
Washington University in St Louis
Investigators
306 investigators, click to expand
Burk Robert D
Chen Zigui
Saller Charles
Tarvin Katherine
Carvalho Andre L
Scapulatempo-Neto Cristovam
Silveira Henrique C
Fregnani José H
Creighton Chad J
Anderson Matthew L
Castro Patricia
Wang Sophia S
Yau Christina
Benz Christopher
Robertson A Gordon
Mungall Karen
Lim Lynette
Bowlby Reanne
Sadeghi Sara
Brooks Denise
Sipahimalani Payal
Mar Richard
Ally Adrian
Clarke Amanda
Mungall Andrew J
Tam Angela
Lee Darlene
Chuah Eric
Schein Jacqueline E
Tse Kane
Kasaian Katayoon
Ma Yussanne
Marra Marco A
Mayo Michael
Balasundaram Miruna
Thiessen Nina
Dhalla Noreen
Carlsen Rebecca
Moore Richard A
Holt Robert A
Jones Steven J M
Wong Tina
Pantazi Angeliki
Parfenov Michael
Kucherlapati Raju
Hadjipanayis Angela
Seidman Jonathan
Kucherlapati Melanie
Ren Xiaojia
Xu Andrew W
Yang Lixing
Park Peter J
Lee Semin
Rabeno Brenda
Huelsenbeck-Dill Lori
Borowsky Mark
Cadungog Mark
Iacocca Mary
Petrelli Nicholas
Swanson Patricia
Ojesina Akinyemi I
Le Xuan
Sandusky George
Adebamowo Sally N
Akeredolu Teniola
Adebamowo Clement
Reynolds Sheila M
Shmulevich Ilya
Shelton Candace
Crain Daniel
Mallery David
Curley Erin
Gardner Johanna
Penny Robert
Morris Scott
Shelton Troy
Liu Jia
Lolla Laxmi
Chudamani Sudha
Wu Ye
Birrer Michael
McLellan Michael D
Bailey Matthew H
Miller Christopher A
Wyczalkowski Matthew A
Fulton Robert S
Fronick Catrina C
Lu Charles
Mardis Elaine R
Appelbaum Elizabeth L
Schmidt Heather K
Fulton Lucinda A
Cordes Matthew G
Li Tiandao
Ding Li
Wilson Richard K
Rader Janet S
Behmaram Behnaz
Uyar Denise
Bradley William
Wrangle John
Pastore Alessandro
Levine Douglas A
Dao Fanny
Gao Jianjiong
Schultz Nikolaus
Sander Chris
Ladanyi Marc
Einstein Mark
Teeter Randall
Benz Stephen
Wentzensen Nicolas
Felau Ina
Zenklusen Jean C
Bodelon Clara
Demchok John A
Yang Liming
Sheth Margi
Ferguson Martin L
Tarnuzzer Roy
Yang Hannah
Schiffman Mark
Zhang Jiashan
Wang Zhining
Davidsen Tanja
Olaniyan Olayinka
Hutter Carolyn M
Sofia Heidi J
Gordenin Dmitry A
Chan Kin
Roberts Steven A
Klimczak Leszek J
Van Waes Carter
Chen Zhong
Saleh Anthony D
Cheng Hui
Parfitt Jeremy
Bartlett John
Albert Monique
Arnaout Angel
Sekhon Harman
Gilbert Sebastien
Peto Myron
Myers Jerome
Harr Jodi
Eckman John
Bergsten Julie
Tucker Kelinda
Zach Leigh Anne
Karlan Beth Y
Lester Jenny
Orsulic Sandra
Sun Qiang
Naresh Rashi
Pihl Todd
Wan Yunhu
Zaren Howard
Sapp Jennifer
Miller Judy
Drwiega Paul
Ojesina Akinyemi I
Murray Bradley A
Zhang Hailei
Cherniack Andrew D
Sougnez Carrie
Pedamallu Chandra Sekhar
Lichtenstein Lee
Meyerson Matthew
Noble Michael S
Heiman David I
Voet Doug
Getz Gad
Saksena Gordon
Kim Jaegil
Shih Juliann
Cho Juok
Lawrence Michael S
Gehlenborg Nils
Lin Pei
Beroukhim Rameen
Frazer Scott
Gabriel Stacey B
Schumacher Steven E
Leraas Kristen M
Lichtenberg Tara M
Zmuda Erik
Bowen Jay
Frick Jessica
Gastier-Foster Julie M
Wise Lisa
Gerken Mark
Ramirez Nilsa C
Danilova Ludmila
Cope Leslie
Baylin Stephen B
Salvesen Helga B
Vellano Christopher P
Ju Zhenlin
Diao Lixia
Zhao Hao
Chong Zechen
Ryan Michael C
Martinez-Ledesma Emmanuel
Verhaak Roeland G
Averett Byers Lauren
Yuan Yuan
Chen Ken
Ling Shiyun
Mills Gordon B
Lu Yiling
Akbani Rehan
Seth Sahil
Liang Han
Wang Jing
Han Leng
Weinstein John N
Bristow Christopher A
Zhang Wei
Mahadeshwar Harshad S
Sun Huandong
Tang Jiabin
Zhang Jianhua
Song Xingzhi
Protopopov Alexei
Shaw Kenna R Mills
Chin Lynda
Olabode Oluwole
Ojesina Akinyemi I
DiSaia Philip
Radenbaugh Amie
Haussler David
Zhu Jingchun
Stuart Josh
Chalise Prabhakar
Koestler Devin
Fridley Brooke L
Godwin Andrew K
Madan Rashna
Ciriello Giovanni
Martinez Cathleen
Higgins Kelly
Bocklage Therese
Auman J Todd
Perou Charles M
Tan Donghui
Parker Joel S
Hoadley Katherine A
Wilkerson Matthew D
Mieczkowski Piotr A
Skelly Tara
Veluvolu Umadevi
Hayes D Neil
Rathmell W Kimryn
Hoyle Alan P
Simons Janae V
Wu Junyuan
Mose Lisle E
Soloway Matthew G
Balu Saianand
Meng Shaowu
Jefferys Stuart R
Bodenheimer Tom
Shi Yan
Roach Jeffrey
Thorne Leigh B
Boice Lori
Huang Mei
Jones Corbin D
Zuna Rosemary
Walker Joan
Gunderson Camille
Snowbarger Carie
Brown David
Moxley Katherine
Moore Kathleen
Andrade Kelsi
Landrum Lisa
Mannel Robert
McMeekin Scott
Johnson Starla
Nelson Tina
Elishaev Esther
Dhir Rajiv
Edwards Robert
Bhargava Rohit
Tiezzi Daniel G
Andrade Jurandyr M
Noushmehr Houtan
Gilberto Carlotti Carlos
Tirapelli Daniela Pretti da Cunha
Weisenberger Daniel J
Van Den Berg David J
Maglinte Dennis T
Bootwalla Moiz S
Lai Phillip H
Triche Timothy
Swisher Elizabeth M
Agnew Kathy J
Shelley Carl Simon
Laird Peter W
Schwarz Julie
Grigsby Perry
Mutch David
Schwarz Julie
Grigsby Perry
Mutch David
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
Published
2017-00-16
Epub
2017-00-23
Pages
378-384
Language
English
Region
England
NLM ID
0410462
PMCID
PMC5354998
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NHGRI NIH HHS · U54 HG003067 · United States
NCI NIH HHS · U24 CA143835 · United States
NCI NIH HHS · U24 CA210950 · United States
NCI NIH HHS · U24 CA143882 · United States
NCI NIH HHS · U24 CA143845 · United States
NCI NIH HHS · U24 CA143799 · United States
NHGRI NIH HHS · U54 HG003273 · United States
NCI NIH HHS · U24 CA144025 · United States
NCI NIH HHS · U24 CA180951 · United States
NCI NIH HHS · U24 CA143840 · United States
NCI NIH HHS · U24 CA210974 · United States
NCI NIH HHS · U24 CA143858 · United States
NCI NIH HHS · U24 CA143848 · United States
NHGRI NIH HHS · U54 HG003079 · United States
NCI NIH HHS · U24 CA210949 · United States
NCI NIH HHS · U24 CA143883 · United States
NCI NIH HHS · U24 CA211006 · United States
NCI NIH HHS · U24 CA143867 · United States
NCI NIH HHS · U24 CA199461 · United States
NCI NIH HHS · U24 CA143866 · United States
NCI NIH HHS · U24 CA143843 · United States
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