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Nature. 2017 Mar 16;543(7645):378-384. doi: 10.1038/nature21386. Epub 2017 Jan 23.

Integrated genomic and molecular characterization of cervical cancer.

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.

Collaborators (306)

Burk RD, Chen Z, Saller C, Tarvin K, Carvalho AL, Scapulatempo-Neto C, Silveira HC, Fregnani JH, Creighton CJ, Anderson ML, Castro P, Wang SS, Yau C, Benz C, Robertson AG, Mungall K, Lim L, Bowlby R, Sadeghi S, Brooks D, Sipahimalani P, Mar R, Ally A, Clarke A, Mungall AJ, Tam A, Lee D, Chuah E, Schein JE, Tse K, Kasaian K, Ma Y, Marra MA, Mayo M, Balasundaram M, Thiessen N, Dhalla N, Carlsen R, Moore RA, Holt RA, Jones SJ, Wong T, Pantazi A, Parfenov M, Kucherlapati R, Hadjipanayis A, Seidman J, Kucherlapati M, Ren X, Xu AW, Yang L, Park PJ, Lee S, Rabeno B, Huelsenbeck-Dill L, Borowsky M, Cadungog M, Iacocca M, Petrelli N, Swanson P, Ojesina AI, Le X, Sandusky G, Adebamowo SN, Akeredolu T, Adebamowo C, Reynolds SM, Shmulevich I, Shelton C, Crain D, Mallery D, Curley E, Gardner J, Penny R, Morris S, Shelton T, Liu J, Lolla L, Chudamani S, Wu Y, Birrer M, McLellan MD, Bailey MH, Miller CA, Wyczalkowski MA, Fulton RS, Fronick CC, Lu C, Mardis ER, Appelbaum EL, Schmidt HK, Fulton LA, Cordes MG, Li T, Ding L, Wilson RK, Rader JS, Behmaram B, Uyar D, Bradley W, Wrangle J, Pastore A, Levine DA, Dao F, Gao J, Schultz N, Sander C, Ladanyi M, Einstein M, Teeter R, Benz S, Wentzensen N, Felau I, Zenklusen JC, Bodelon C, Demchok JA, Yang L, Sheth M, Ferguson ML, Tarnuzzer R, Yang H, Schiffman M, Zhang J, Wang Z, Davidsen T, Olaniyan O, Hutter CM, Sofia HJ, Gordenin DA, Chan K, Roberts SA, Klimczak LJ, Van Waes C, Chen Z, Saleh AD, Cheng H, Parfitt J, Bartlett J, Albert M, Arnaout A, Sekhon H, Gilbert S, Peto M, Myers J, Harr J, Eckman J, Bergsten J, Tucker K, Zach LA, Karlan BY, Lester J, Orsulic S, Sun Q, Naresh R, Pihl T, Wan Y, Zaren H, Sapp J, Miller J, Drwiega P, Ojesina AI, Murray BA, Zhang H, Cherniack AD, Sougnez C, Pedamallu CS, Lichtenstein L, Meyerson M, Noble MS, Heiman DI, Voet D, Getz G, Saksena G, Kim J, Shih J, Cho J, Lawrence MS, Gehlenborg N, Lin P, Beroukhim R, Frazer S, Gabriel SB, Schumacher SE, Leraas KM, Lichtenberg TM, Zmuda E, Bowen J, Frick J, Gastier-Foster JM, Wise L, Gerken M, Ramirez NC, Danilova L, Cope L, Baylin SB, Salvesen HB, Vellano CP, Ju Z, Diao L, Zhao H, Chong Z, Ryan MC, Martinez-Ledesma E, Verhaak RG, Averett Byers L, Yuan Y, Chen K, Ling S, Mills GB, Lu Y, Akbani R, Seth S, Liang H, Wang J, Han L, Weinstein JN, Bristow CA, Zhang W, Mahadeshwar HS, Sun H, Tang J, Zhang J, Song X, Protopopov A, Shaw KR, Chin L, Olabode O, Ojesina AI, DiSaia P, Radenbaugh A, Haussler D, Zhu J, Stuart J, Chalise P, Koestler D, Fridley BL, Godwin AK, Madan R, Ciriello G, Martinez C, Higgins K, Bocklage T, Auman JT, Perou CM, Tan D, Parker JS, Hoadley KA, Wilkerson MD, Mieczkowski PA, Skelly T, Veluvolu U, Hayes DN, Rathmell WK, Hoyle AP, Simons JV, Wu J, Mose LE, Soloway MG, Balu S, Meng S, Jefferys SR, Bodenheimer T, Shi Y, Roach J, Thorne LB, Boice L, Huang M, Jones CD, Zuna R, Walker J, Gunderson C, Snowbarger C, Brown D, Moxley K, Moore K, Andrade K, Landrum L, Mannel R, McMeekin S, Johnson S, Nelson T, Elishaev E, Dhir R, Edwards R, Bhargava R, Tiezzi DG, Andrade JM, Noushmehr H, Gilberto Carlotti C, Tirapelli DP, Weisenberger DJ, Van Den Berg DJ, Maglinte DT, Bootwalla MS, Lai PH, Triche T, Swisher EM, Agnew KJ, Shelley CS, Laird PW, Schwarz J, Grigsby P, Mutch D, Schwarz J, Grigsby P, Mutch D.

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.

PMID:
28112728
PMCID:
PMC5354998
DOI:
10.1038/nature21386
[Indexed for MEDLINE]
Free PMC Article

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