Abstract
We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.
Original language | English |
---|---|
Pages (from-to) | 67-73 |
Number of pages | 7 |
Journal | Nature |
Volume | 497 |
Issue number | 7447 |
DOIs | |
State | Published - 2013 |
Externally published | Yes |
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In: Nature, Vol. 497, No. 7447, 2013, p. 67-73.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Integrated genomic characterization of endometrial carcinoma
AU - Getz, Gad
AU - Gabriel, Stacey B.
AU - Cibulskis, Kristian
AU - Lander, Eric
AU - Sivachenko, Andrey
AU - Sougnez, Carrie
AU - Lawrence, Mike
AU - Kandoth, Cyriac
AU - Dooling, David
AU - Fulton, Robert
AU - Fulton, Lucinda
AU - Kalicki-Veizer, Joelle
AU - McLellan, Michael D.
AU - O'Laughlin, Michelle
AU - Schmidt, Heather
AU - Wilson, Richard K.
AU - Ye, Kai
AU - Li, Ding
AU - Ally, Adrian
AU - Balasundaram, Miruna
AU - Birol, Inanc
AU - Butterfield, Yaron S.N.
AU - Carlsen, Rebecca
AU - Carter, Candace
AU - Chu, Andy
AU - Chuah, Eric
AU - Chun, Hye Jung E.
AU - Dhalla, Noreen
AU - Guin, Ranabir
AU - Hirst, Carrie
AU - Holt, Robert A.
AU - Jones, Steven J.M.
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Marra, Marco A.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Mungall, Andrew J.
AU - Plettner, Patrick
AU - Schein, Jacqueline E.
AU - Sipahimalani, Payal
AU - Tam, Angela
AU - Varhol, Richard J.
AU - Gordon Robertson, A.
AU - Cherniack, Andrew D.
AU - Pashtan, Itai
AU - Saksena, Gordon
AU - Onofrio, Robert C.
AU - Schumacher, Steven E.
AU - Tabak, Barbara
AU - Carter, Scott L.
AU - Hernandez, Bryan
AU - Gentry, Jeff
AU - Salvesen, Helga B.
AU - Ardlie, Kristin
AU - Winckler, Wendy
AU - Beroukhim, Rameen
AU - Meyerson, Matthew
AU - Hadjipanayis, Angela
AU - Lee, Semin
AU - Mahadeshwar, Harshad S.
AU - Park, Peter
AU - Protopopov, Alexei
AU - Ren, Xiaojia
AU - Seth, Sahil
AU - Song, Xingzhi
AU - Tang, Jiabin
AU - Xi, Ruibin
AU - Yang, Lixing
AU - Dong, Zeng
AU - Kucherlapati, Raju
AU - Chin, Lynda
AU - Zhang, Jianhua
AU - Todd Auman, J.
AU - Balu, Saianand
AU - Bodenheimer, Tom
AU - Buda, Elizabeth
AU - Neil Hayes, D.
AU - Hoyle, Alan P.
AU - Jefferys, Stuart R.
AU - Jones, Corbin D.
AU - Meng, Shaowu
AU - Mieczkowski, Piotr A.
AU - Mose, Lisle E.
AU - Parker, Joel S.
AU - Perou, Charles M.
AU - Roach, Jeff
AU - Yan, Shi
AU - Simons, Janae V.
AU - Soloway, Mathew G.
AU - Tan, Donghui
AU - Topal, Michael D.
AU - Waring, Scot
AU - Wu, Junyuan
AU - Hoadley, Katherine A.
AU - Baylin, Stephen B.
AU - Bootwalla, Moiz S.
AU - Lai, Phillip H.
AU - Triche, Timothy J.
AU - Van Den Berg, David J.
AU - Weisenberger, Daniel J.
AU - Laird, Peter W.
AU - Shen, Hui
AU - Cho, Juok
AU - Dicara, Daniel
AU - Frazer, Scott
AU - Heiman, David
AU - Jing, Rui
AU - Lin, Pei
AU - Mallard, Will
AU - Stojanov, Petar
AU - Voet, Doug
AU - Zhang, Hailei
AU - Zou, Lihua
AU - Noble, Michael
AU - Reynolds, Sheila M.
AU - Shmulevich, Ilya
AU - Arman Aksoy, B.
AU - Antipin, Yevgeniy
AU - Ciriello, Giovanni
AU - Dresdner, Gideon
AU - Gao, Jianjiong
AU - Gross, Benjamin
AU - Jacobsen, Anders
AU - Ladanyi, Marc
AU - Reva, Boris
AU - Sander, Chris
AU - Sinha, Rileen
AU - Onur Sumer, S.
AU - Taylor, Barry S.
AU - Cerami, Ethan
AU - Weinhold, Nils
AU - Schultz, Nikolaus
AU - Shen, Ronglai
AU - Benz, Stephen
AU - Goldstein, Ted
AU - Haussler, David
AU - Ng, Sam
AU - Szeto, Christopher
AU - Stuart, Joshua
AU - Benz, Christopher C.
AU - Yau, Christina
AU - Zhang, Wei
AU - Annala, Matti
AU - Broom, Bradley M.
AU - Casasent, Tod D.
AU - Ju, Zhenlin
AU - Liang, Han
AU - Liu, Guoyan
AU - Lu, Yiling
AU - Unruh, Anna K.
AU - Wakefield, Chris
AU - Weinstein, John N.
AU - Zhang, Nianxiang
AU - Liu, Yuexin
AU - Broaddus, Russell
AU - Akbani, Rehan
AU - Mills, Gordon B.
AU - Adams, Christopher
AU - Barr, Thomas
AU - Black, Aaron D.
AU - Bowen, Jay
AU - Deardurff, John
AU - Frick, Jessica
AU - Gastier-Foster, Julie M.
AU - Grossman, Thomas
AU - Harper, Hollie A.
AU - Hart-Kothari, Melissa
AU - Helsel, Carmen
AU - Hobensack, Aaron
AU - Kuck, Harkness
AU - Kneile, Kelley
AU - Leraas, Kristen M.
AU - Lichtenberg, Tara M.
AU - McAllister, Cynthia
AU - Pyatt, Robert E.
AU - Ramirez, Nilsa C.
AU - Tabler, Teresa R.
AU - Vanhoose, Nathan
AU - White, Peter
AU - Wise, Lisa
AU - Zmuda, Erik
AU - Barnabas, Nandita
AU - Berry-Green, Charlenia
AU - Blanc, Victoria
AU - Boice, Lori
AU - Button, Michael
AU - Farkas, Adam
AU - Green, Alex
AU - MacKenzie, Jean
AU - Nicholson, Dana
AU - Kalloger, Steve E.
AU - Blake Gilks, C.
AU - Karlan, Beth Y.
AU - Lester, Jenny
AU - Orsulic, Sandra
AU - Borowsky, Mark
AU - Cadungog, Mark
AU - Czerwinski, Christine
AU - Huelsenbeck-Dill, Lori
AU - Iacocca, Mary
AU - Petrelli, Nicholas
AU - Rabeno, Brenda
AU - Witkin, Gary
AU - Nemirovich-Danchenko, Elena
AU - Potapova, Olga
AU - Rotin, Daniil
AU - Berchuck, Andrew
AU - Birrer, Michael
AU - Disaia, Phillip
AU - Monovich, Laura
AU - Curley, Erin
AU - Gardner, Johanna
AU - Mallery, David
AU - Penny, Robert
AU - Dowdy, Sean C.
AU - Winterhoff, Boris
AU - Dao, Linda
AU - Gostout, Bobbie
AU - Meuter, Alexandra
AU - Teoman, Attila
AU - Dao, Fanny
AU - Olvera, Narciso
AU - Bogomolniy, Faina
AU - Garg, Karuna
AU - Soslow, Robert A.
AU - Abramov, Mikhail
AU - Bartlett, John M.S.
AU - Kodeeswaran, Sugy
AU - Parfitt, Jeremy
AU - Moiseenko, Fedor
AU - Clarke, Blaise A.
AU - Goodman, Marc T.
AU - Carney, Michael E.
AU - Matsuno, Rayna K.
AU - Fisher, Jennifer
AU - Huang, Mei
AU - Kimryn Rathmell, W.
AU - Thorne, Leigh
AU - Van Le, Linda
AU - Dhir, Rajiv
AU - Edwards, Robert
AU - Elishaev, Esther
AU - Zorn, Kristin
AU - Goodfellow, Paul J.
AU - Mutch, David
AU - Kahn, Ari B.
AU - Bell, Daphne W.
AU - Pollock, Pamela M.
AU - Wang, Chen
AU - Wheeler, David
AU - Shinbrot, Eve
AU - Gordon Robertson, A.
AU - Ding, Li
AU - Blake Gilks, C.
AU - Mardis, Elaine R.
AU - Ayala, Brenda
AU - Chu, Anna L.
AU - Jensen, Mark A.
AU - Kothiyal, Prachi
AU - Pihl, Todd D.
AU - Pontius, Joan
AU - Pot, David A.
AU - Snyder, Eric E.
AU - Srinivasan, Deepak
AU - Mills Shaw, Kenna R.
AU - Sheth, Margi
AU - Davidsen, Tanja
AU - Eley, Greg
AU - Ferguson, Martin L.
AU - Yang, Liming
AU - Guyer, Mark S.
AU - Ozenberger, Bradley A.
AU - Sofia, Heidi J.
AU - Gordon Robertson, A.
AU - Levine, Douglas A.
N1 - Funding Information: Acknowledgements We wish to thank all patients and families who contributed to this study.WethankM.Shethand L.Lundfor administrativecoordinationofTCGAactivities, G. Monemvasitis for editing the manuscript, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the US National Institutes of Health: 5U24CA143799-04, 5U24CA143835-04, 5U24CA143840-04, 5U24CA143843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA143866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067-11, U54HG003079-10 and U54HG003273-10.
PY - 2013
Y1 - 2013
N2 - We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.
AB - We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array-and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.
UR - http://www.scopus.com/inward/record.url?scp=84877254190&partnerID=8YFLogxK
U2 - 10.1038/nature12113
DO - 10.1038/nature12113
M3 - Article
C2 - 23636398
AN - SCOPUS:84877254190
SN - 0028-0836
VL - 497
SP - 67
EP - 73
JO - Nature
JF - Nature
IS - 7447
ER -