Abstract
To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase μ (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
| Original language | English |
|---|---|
| Pages (from-to) | 330-337 |
| Number of pages | 8 |
| Journal | Nature |
| Volume | 487 |
| Issue number | 7407 |
| DOIs | |
| State | Published - 19 Jul 2012 |
| Externally published | Yes |
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In: Nature, Vol. 487, No. 7407, 19.07.2012, p. 330-337.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive molecular characterization of human colon and rectal cancer
AU - Muzny, Donna M.
AU - Bainbridge, Matthew N.
AU - Chang, Kyle
AU - Dinh, Huyen H.
AU - Drummond, Jennifer A.
AU - Fowler, Gerald
AU - Kovar, Christie L.
AU - Lewis, Lora R.
AU - Morgan, Margaret B.
AU - Newsham, Irene F.
AU - Reid, Jeffrey G.
AU - Santibanez, Jireh
AU - Shinbrot, Eve
AU - Trevino, Lisa R.
AU - Wu, Yuan Qing
AU - Wang, Min
AU - Gunaratne, Preethi
AU - Donehower, Lawrence A.
AU - Creighton, Chad J.
AU - Wheeler, David A.
AU - Gibbs, Richard A.
AU - Lawrence, Michael S.
AU - Voet, Douglas
AU - Jing, Rui
AU - Cibulskis, Kristian
AU - Sivachenko, Andrey
AU - Stojanov, Petar
AU - McKenna, Aaron
AU - Lander, Eric S.
AU - Gabriel, Stacey
AU - Ding, Li
AU - Fulton, Robert S.
AU - Koboldt, Daniel C.
AU - Wylie, Todd
AU - Walker, Jason
AU - Dooling, David J.
AU - Fulton, Lucinda
AU - Delehaunty, Kim D.
AU - Fronick, Catrina C.
AU - Demeter, Ryan
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Chu, Andy
AU - Chun, Hye Jung E.
AU - Mungall, Andrew J.
AU - Pleasance, Erin
AU - Gordon Robertson, A.
AU - Stoll, Dominik
AU - Balasundaram, Miruna
AU - Birol, Inanc
AU - Butterfield, Yaron S.N.
AU - Chuah, Eric
AU - Coope, Robin J.N.
AU - Dhalla, Noreen
AU - Guin, Ranabir
AU - Hirst, Carrie
AU - Hirst, Martin
AU - Holt, Robert A.
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Schein, Jacqueline E.
AU - Slobodan, Jared R.
AU - Tam, Angela
AU - Thiessen, Nina
AU - Varhol, Richard
AU - Zeng, Thomas
AU - Zhao, Yongjun
AU - Jones, Steven J.M.
AU - Marra, Marco A.
AU - Bass, Adam J.
AU - Ramos, Alex H.
AU - Saksena, Gordon
AU - Cherniack, Andrew D.
AU - Schumacher, Stephen E.
AU - Tabak, Barbara
AU - Carter, Scott L.
AU - Pho, Nam H.
AU - Nguyen, Huy
AU - Onofrio, Robert C.
AU - Crenshaw, Andrew
AU - Ardlie, Kristin
AU - Beroukhim, Rameen
AU - Winckler, Wendy
AU - Meyerson, Matthew
AU - Protopopov, Alexei
AU - Hadjipanayis, Angela
AU - Lee, Eunjung
AU - Xi, Ruibin
AU - Yang, Lixing
AU - Ren, Xiaojia
AU - Sathiamoorthy, Narayanan
AU - Chen, Peng Chieh
AU - Haseley, Psalm
AU - Xiao, Yonghong
AU - Lee, Semin
AU - Seidman, Jonathan
AU - Chin, Lynda
AU - Park, Peter J.
AU - Kucherlapati, Raju
AU - Todd Auman, J.
AU - Hoadley, Katherine A.
AU - Du, Ying
AU - Wilkerson, Matthew D.
AU - Shi, Yan
AU - Liquori, Christina
AU - Meng, Shaowu
AU - Li, Ling
AU - Turman, Yidi J.
AU - Topal, Michael D.
AU - Tan, Donghui
AU - Waring, Scot
AU - Buda, Elizabeth
AU - Walsh, Jesse
AU - Jones, Corbin D.
AU - Mieczkowski, Piotr A.
AU - Singh, Darshan
AU - Wu, Junyuan
AU - Gulabani, Anisha
AU - Dolina, Peter
AU - Bodenheimer, Tom
AU - Hoyle, Alan P.
AU - Simons, Janae V.
AU - Soloway, Matthew
AU - Mose, Lisle E.
AU - Jefferys, Stuart R.
AU - Balu, Saianand
AU - O'Connor, Brian D.
AU - Prins, Jan F.
AU - Chiang, Derek Y.
AU - Neil Hayes, D.
AU - Perou, Charles M.
AU - Hinoue, Toshinori
AU - Weisenberger, Daniel J.
AU - Maglinte, Dennis T.
AU - Pan, Fei
AU - Berman, Benjamin P.
AU - Van Den Berg, David J.
AU - Shen, Hui
AU - Triche, Timothy
AU - Baylin, Stephen B.
AU - Laird, Peter W.
AU - Getz, Gad
AU - Noble, Michael
AU - Voat, Doug
AU - Gehlenborg, Nils
AU - Dicara, Daniel
AU - Zhang, Juinhua
AU - Zhang, Hailei
AU - Wu, Chang Jiun
AU - Liu, Spring Yingchun
AU - Shukla, Sachet
AU - Zhou, Lihua
AU - Lin, Pei
AU - Park, Richard W.
AU - Nazaire, Marc Danie
AU - Robinson, Jim
AU - Thorvaldsdottir, Helga
AU - Mesirov, Jill
AU - Thorsson, Vesteinn
AU - Reynolds, Sheila M.
AU - Bernard, Brady
AU - Kreisberg, Richard
AU - Lin, Jake
AU - Iype, Lisa
AU - Bressler, Ryan
AU - Erkkilä, Timo
AU - Gundapuneni, Madhumati
AU - Liu, Yuexin
AU - Norberg, Adam
AU - Robinson, Tom
AU - Yang, Da
AU - Zhang, Wei
AU - Shmulevich, Ilya
AU - De Ronde, Jorma J.
AU - Schultz, Nikolaus
AU - Cerami, Ethan
AU - Ciriello, Giovanni
AU - Goldberg, Arthur P.
AU - Gross, Benjamin
AU - Jacobsen, Anders
AU - Gao, Jianjiong
AU - Kaczkowski, Bogumil
AU - Sinha, Rileen
AU - Arman Aksoy, B.
AU - Antipin, Yevgeniy
AU - Reva, Boris
AU - Shen, Ronglai
AU - Taylor, Barry S.
AU - Ladanyi, Marc
AU - Sander, Chris
AU - Akbani, Rehan
AU - Zhang, Nianxiang
AU - Broom, Bradley M.
AU - Casasent, Tod
AU - Unruh, Anna
AU - Wakefield, Chris
AU - Hamilton, Stanley R.
AU - Craig Cason, R.
AU - Baggerly, Keith A.
AU - Weinstein, John N.
AU - Haussler, David
AU - Benz, Christopher C.
AU - Stuart, Joshua M.
AU - Benz, Stephen C.
AU - Zachary Sanborn, J.
AU - Vaske, Charles J.
AU - Zhu, Jingchun
AU - Szeto, Christopher
AU - Scott, Gary K.
AU - Yau, Christina
AU - Ng, Sam
AU - Goldstein, Ted
AU - Ellrott, Kyle
AU - Collisson, Eric
AU - Cozen, Aaron E.
AU - Zerbino, Daniel
AU - Wilks, Christopher
AU - Craft, Brian
AU - Spellman, Paul
AU - Penny, Robert
AU - Shelton, Troy
AU - Hatfield, Martha
AU - Morris, Scott
AU - Yena, Peggy
AU - Shelton, Candace
AU - Sherman, Mark
AU - Paulauskis, Joseph
AU - Gastier-Foster, Julie M.
AU - Bowen, Jay
AU - Ramirez, Nilsa C.
AU - Black, Aaron
AU - Pyatt, Robert
AU - Wise, Lisa
AU - White, Peter
AU - Bertagnolli, Monica
AU - Brown, Jen
AU - Chan, Timothy A.
AU - Chu, Gerald C.
AU - Czerwinski, Christine
AU - Denstman, Fred
AU - Dhir, Rajiv
AU - Dörner, Arnulf
AU - Fuchs, Charles S.
AU - Guillem, Jose G.
AU - Iacocca, Mary
AU - Juhl, Hartmut
AU - Kaufman, Andrew
AU - Iii, Bernard Kohl
AU - Van Le, Xuan
AU - Mariano, Maria C.
AU - Medina, Elizabeth N.
AU - Meyers, Michael
AU - Nash, Garrett M.
AU - Paty, Phillip B.
AU - Petrelli, Nicholas
AU - Rabeno, Brenda
AU - Richards, William G.
AU - Solit, David
AU - Swanson, Pat
AU - Temple, Larissa
AU - Tepper, Joel E.
AU - Thorp, Richard
AU - Vakiani, Efsevia
AU - Weiser, Martin R.
AU - Willis, Joseph E.
AU - Witkin, Gary
AU - Zeng, Zhaoshi
AU - Zinner, Michael J.
AU - Zornig, Carsten
AU - Jensen, Mark A.
AU - Sfeir, Robert
AU - Kahn, Ari B.
AU - Chu, Anna L.
AU - Kothiyal, Prachi
AU - Wang, Zhining
AU - Snyder, Eric E.
AU - Pontius, Joan
AU - Pihl, Todd D.
AU - Ayala, Brenda
AU - Backus, Mark
AU - Walton, Jessica
AU - Whitmore, Jon
AU - Baboud, Julien
AU - Berton, Dominique L.
AU - Nicholls, Matthew C.
AU - Srinivasan, Deepak
AU - Raman, Rohini
AU - Girshik, Stanley
AU - Kigonya, Peter A.
AU - Alonso, Shelley
AU - Sanbhadti, Rashmi N.
AU - Barletta, Sean P.
AU - Greene, John M.
AU - Pot, David A.
AU - Shaw, Kenna R.Mills
AU - Dillon, Laura A.L.
AU - Buetow, Ken
AU - Davidsen, Tanja
AU - Demchok, John A.
AU - Eley, Greg
AU - Ferguson, Martin
AU - Fielding, Peter
AU - Schaefer, Carl
AU - Sheth, Margi
AU - Yang, Liming
AU - Guyer, Mark S.
AU - Ozenberger, Bradley A.
AU - Palchik, Jacqueline D.
AU - Peterson, Jane
AU - Sofia, Heidi J.
AU - Thomson., Elizabeth
N1 - Funding Information: Acknowledgements This work was supported by the following grants from the National Institutes of Health: U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, U24CA144025, U54HG003067, U54HG003079 and U54HG003273.
PY - 2012/7/19
Y1 - 2012/7/19
N2 - To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase μ (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
AB - To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase μ (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
UR - http://www.scopus.com/inward/record.url?scp=84863922124&partnerID=8YFLogxK
U2 - 10.1038/nature11252
DO - 10.1038/nature11252
M3 - Article
C2 - 22810696
AN - SCOPUS:84863922124
SN - 0028-0836
VL - 487
SP - 330
EP - 337
JO - Nature
JF - Nature
IS - 7407
ER -