Integrated genomic analyses of ovarian carcinoma

D. Bell; A. Berchuck; M. Birrer; J. Chien; D. W. Cramer; F. Dao; R. Dhir; P. Disaia; H. Gabra; P. Glenn; A. K. Godwin; J. Gross; L. Hartmann; M. Huang; D. G. Huntsman; M. Iacocca; M. Imielinski; S. Kalloger; B. Y. Karlan; D. A. Levine; G. B. Mills; C. Morrison; D. Mutch; N. Olvera; S. Orsulic; K. Park; N. Petrelli; B. Rabeno; J. S. Rader; B. I. Sikic; K. Smith-Mccune; A. K. Sood; D. Bowtell; R. Penny; J. R. Testa; K. Chang; H. H. Dinh; J. A. Drummond; G. Fowler; P. Gunaratne; A. C. Hawes; C. L. Kovar; L. R. Lewis; M. B. Morgan; I. F. Newsham; J. Santibanez; J. G. Reid; L. R. Trevino; Y. Q. Wu; M. Wang; D. M. Muzny; D. A. Wheeler; R. A. Gibbs; G. Getz; M. S. Lawrence; K. Cibulskis; A. Y. Sivachenko; C. Sougnez; D. Voet; J. Wilkinson; T. Bloom; K. Ardlie; T. Fennell; J. Baldwin; S. Gabriel; E. S. Lander; L. Ding; R. S. Fulton; D. C. Koboldt; M. D. McLellan; T. Wylie; J. Walker; M. O'Laughlin; D. J. Dooling; L. Fulton; R. Abbott; N. D. Dees; Q. Zhang; C. Kandoth; M. Wendl; W. Schierding; D. Shen; C. C. Harris; H. Schmidt; J. Kalicki; K. D. Delehaunty; C. C. Fronick; R. Demeter; L. Cook; J. W. Wallis; L. Lin; V. J. Magrini; J. S. Hodges; J. M. Eldred; S. M. Smith; C. S. Pohl; F. Vandin; B. J. Raphael; G. M. Weinstock; E. R. Mardis; R. K. Wilson; M. Meyerson; W. Winckler; R. G.W. Verhaak; S. L. Carter; C. H. Mermel; G. Saksena; H. Nguyen; R. C. Onofrio; D. Hubbard; S. Gupta; A. Crenshaw; A. H. Ramos; L. Chin; A. Protopopov; Jinghui Zhang; T. M. Kim; I. Perna; Y. Xiao; H. Zhang; G. Ren; N. Sathiamoorthy; R. W. Park; E. Lee; P. J. Park; R. Kucherlapati; D. M. Absher; L. Waite; G. Sherlock; J. D. Brooks; J. Z. Li; J. Xu; R. M. Myers; P. W. Laird; L. Cope; J. G. Herman; H. Shen; D. J. Weisenberger; H. Noushmehr; F. Pan; T. Triche; B. P. Berman; D. J. Van Den Berg; J. Buckley; S. B. Baylin; P. T. Spellman; E. Purdom; P. Neuvial; H. Bengtsson; L. R. Jakkula; S. Durinck; J. Han; S. Dorton; H. Marr; Y. G. Choi; V. Wang; N. J. Wang; J. Ngai; J. G. Conboy; B. Parvin; H. S. Feiler; T. P. Speed; J. W. Gray; N. D. Socci; Y. Liang; B. S. Taylor; N. Schultz; L. Borsu; A. E. Lash; C. Brennan; A. Viale; C. Sander; M. Ladanyi; K. A. Hoadley; S. Meng; Y. Du; Y. Shi; L. Li; Y. J. Turman; D. Zang; E. B. Helms; S. Balu; X. Zhou; J. Wu; M. D. Topal; D. N. Hayes; C. M. Perou; C. J. Wu; S. Shukla; A. Sivachenko; R. Jing; Y. Liu; M. Noble; H. Carter; D. Kim; R. Karchin; J. E. Korkola; L. M. Heiser; R. J. Cho; Z. Hu; E. Cerami; A. Olshen; B. Reva; Y. Antipin; R. Shen; P. Mankoo; R. Sheridan; G. Ciriello; W. K. Chang; J. A. Bernanke; D. Haussler; C. C. Benz; J. M. Stuart; S. C. Benz; J. Z. Sanborn; C. J. Vaske; J. Zhu; C. Szeto; G. K. Scott; C. Yau; M. D. Wilkerson; N. Zhang; R. Akbani; K. A. Baggerly; W. K. Yung; J. N. Weinstein; T. Shelton; D. Grimm; M. Hatfield; S. Morris; P. Yena; P. Rhodes; M. Sherman; J. Paulauskis; S. Millis; A. Kahn; J. M. Greene; R. Sfeir; M. A. Jensen; J. Chen; J. Whitmore; S. Alonso; J. Jordan; A. Chu; A. Barker; C. Compton; G. Eley; M. Ferguson; P. Fielding; D. S. Gerhard; R. Myles; C. Schaefer; K. R. Mills Shaw; J. Vaught; J. B. Vockley; P. J. Good; M. S. Guyer; B. Ozenberger; J. Peterson; E. Thomson

doi:10.1038/nature10166

Integrated genomic analyses of ovarian carcinoma

D. Bell, A. Berchuck, M. Birrer, J. Chien, D. W. Cramer, F. Dao, R. Dhir, P. Disaia, H. Gabra, P. Glenn, A. K. Godwin, J. Gross, L. Hartmann, M. Huang, D. G. Huntsman, M. Iacocca, M. Imielinski, S. Kalloger, B. Y. Karlan, D. A. LevineG. B. Mills, C. Morrison, D. Mutch, N. Olvera, S. Orsulic, K. Park, N. Petrelli, B. Rabeno, J. S. Rader, B. I. Sikic, K. Smith-Mccune, A. K. Sood, D. Bowtell, R. Penny, J. R. Testa, K. Chang, H. H. Dinh, J. A. Drummond, G. Fowler, P. Gunaratne, A. C. Hawes, C. L. Kovar, L. R. Lewis, M. B. Morgan, I. F. Newsham, J. Santibanez, J. G. Reid, L. R. Trevino, Y. Q. Wu, M. Wang, D. M. Muzny, D. A. Wheeler, R. A. Gibbs, G. Getz, M. S. Lawrence, K. Cibulskis, A. Y. Sivachenko, C. Sougnez, D. Voet, J. Wilkinson, T. Bloom, K. Ardlie, T. Fennell, J. Baldwin, S. Gabriel, E. S. Lander, L. Ding, R. S. Fulton, D. C. Koboldt, M. D. McLellan, T. Wylie, J. Walker, M. O'Laughlin, D. J. Dooling, L. Fulton, R. Abbott, N. D. Dees, Q. Zhang, C. Kandoth, M. Wendl, W. Schierding, D. Shen, C. C. Harris, H. Schmidt, J. Kalicki, K. D. Delehaunty, C. C. Fronick, R. Demeter, L. Cook, J. W. Wallis, L. Lin, V. J. Magrini, J. S. Hodges, J. M. Eldred, S. M. Smith, C. S. Pohl, F. Vandin, B. J. Raphael, G. M. Weinstock, E. R. Mardis, R. K. Wilson, M. Meyerson, W. Winckler, R. G.W. Verhaak, S. L. Carter, C. H. Mermel, G. Saksena, H. Nguyen, R. C. Onofrio, D. Hubbard, S. Gupta, A. Crenshaw, A. H. Ramos, L. Chin, A. Protopopov, Jinghui Zhang, T. M. Kim, I. Perna, Y. Xiao, H. Zhang, G. Ren, N. Sathiamoorthy, R. W. Park, E. Lee, P. J. Park, R. Kucherlapati, D. M. Absher, L. Waite, G. Sherlock, J. D. Brooks, J. Z. Li, J. Xu, R. M. Myers, P. W. Laird, L. Cope, J. G. Herman, H. Shen, D. J. Weisenberger, H. Noushmehr, F. Pan, T. Triche, B. P. Berman, D. J. Van Den Berg, J. Buckley, S. B. Baylin, P. T. Spellman^*, E. Purdom, P. Neuvial, H. Bengtsson, L. R. Jakkula, S. Durinck, J. Han, S. Dorton, H. Marr, Y. G. Choi, V. Wang, N. J. Wang, J. Ngai, J. G. Conboy, B. Parvin, H. S. Feiler, T. P. Speed, J. W. Gray, N. D. Socci, Y. Liang, B. S. Taylor, N. Schultz, L. Borsu, A. E. Lash, C. Brennan, A. Viale, C. Sander, M. Ladanyi, K. A. Hoadley, S. Meng, Y. Du, Y. Shi, L. Li, Y. J. Turman, D. Zang, E. B. Helms, S. Balu, X. Zhou, J. Wu, M. D. Topal, D. N. Hayes, C. M. Perou, C. J. Wu, S. Shukla, A. Sivachenko, R. Jing, Y. Liu, M. Noble, H. Carter, D. Kim, R. Karchin, J. E. Korkola, L. M. Heiser, R. J. Cho, Z. Hu, E. Cerami, A. Olshen, B. Reva, Y. Antipin, R. Shen, P. Mankoo, R. Sheridan, G. Ciriello, W. K. Chang, J. A. Bernanke, D. Haussler, C. C. Benz, J. M. Stuart, S. C. Benz, J. Z. Sanborn, C. J. Vaske, J. Zhu, C. Szeto, G. K. Scott, C. Yau, M. D. Wilkerson, N. Zhang, R. Akbani, K. A. Baggerly, W. K. Yung, J. N. Weinstein, T. Shelton, D. Grimm, M. Hatfield, S. Morris, P. Yena, P. Rhodes, M. Sherman, J. Paulauskis, S. Millis, A. Kahn, J. M. Greene, R. Sfeir, M. A. Jensen, J. Chen, J. Whitmore, S. Alonso, J. Jordan, A. Chu, A. Barker, C. Compton, G. Eley, M. Ferguson, P. Fielding, D. S. Gerhard, R. Myles, C. Schaefer, K. R. Mills Shaw, J. Vaught, J. B. Vockley, P. J. Good, M. S. Guyer, B. Ozenberger, J. Peterson, E. Thomson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6074 Scopus citations

Abstract

A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Original language	English
Pages (from-to)	609-615
Number of pages	7
Journal	Nature
Volume	474
Issue number	7353
DOIs	https://doi.org/10.1038/nature10166
State	Published - 30 Jun 2011
Externally published	Yes

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10.1038/nature10166

Cite this

Bell, D., Berchuck, A., Birrer, M., Chien, J., Cramer, D. W., Dao, F., Dhir, R., Disaia, P., Gabra, H., Glenn, P., Godwin, A. K., Gross, J., Hartmann, L., Huang, M., Huntsman, D. G., Iacocca, M., Imielinski, M., Kalloger, S., Karlan, B. Y., ... Thomson, E. (2011). Integrated genomic analyses of ovarian carcinoma. Nature, 474(7353), 609-615. https://doi.org/10.1038/nature10166

@article{fc808ba9287941fba7402884fe4456e5,

title = "Integrated genomic analyses of ovarian carcinoma",

abstract = "A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.",

author = "D. Bell and A. Berchuck and M. Birrer and J. Chien and Cramer, {D. W.} and F. Dao and R. Dhir and P. Disaia and H. Gabra and P. Glenn and Godwin, {A. K.} and J. Gross and L. Hartmann and M. Huang and Huntsman, {D. G.} and M. Iacocca and M. Imielinski and S. Kalloger and Karlan, {B. Y.} and Levine, {D. A.} and Mills, {G. B.} and C. Morrison and D. Mutch and N. Olvera and S. Orsulic and K. Park and N. Petrelli and B. Rabeno and Rader, {J. S.} and Sikic, {B. I.} and K. Smith-Mccune and Sood, {A. K.} and D. Bowtell and R. Penny and Testa, {J. R.} and K. Chang and Dinh, {H. H.} and Drummond, {J. A.} and G. Fowler and P. Gunaratne and Hawes, {A. C.} and Kovar, {C. L.} and Lewis, {L. R.} and Morgan, {M. B.} and Newsham, {I. F.} and J. Santibanez and Reid, {J. G.} and Trevino, {L. R.} and Wu, {Y. Q.} and M. Wang and Muzny, {D. M.} and Wheeler, {D. A.} and Gibbs, {R. A.} and G. Getz and Lawrence, {M. S.} and K. Cibulskis and Sivachenko, {A. Y.} and C. Sougnez and D. Voet and J. Wilkinson and T. Bloom and K. Ardlie and T. Fennell and J. Baldwin and S. Gabriel and Lander, {E. S.} and L. Ding and Fulton, {R. S.} and Koboldt, {D. C.} and McLellan, {M. D.} and T. Wylie and J. Walker and M. O'Laughlin and Dooling, {D. J.} and L. Fulton and R. Abbott and Dees, {N. D.} and Q. Zhang and C. Kandoth and M. Wendl and W. Schierding and D. Shen and Harris, {C. C.} and H. Schmidt and J. Kalicki and Delehaunty, {K. D.} and Fronick, {C. C.} and R. Demeter and L. Cook and Wallis, {J. W.} and L. Lin and Magrini, {V. J.} and Hodges, {J. S.} and Eldred, {J. M.} and Smith, {S. M.} and Pohl, {C. S.} and F. Vandin and Raphael, {B. J.} and Weinstock, {G. M.} and Mardis, {E. R.} and Wilson, {R. K.} and M. Meyerson and W. Winckler and Verhaak, {R. G.W.} and Carter, {S. L.} and Mermel, {C. H.} and G. Saksena and H. Nguyen and Onofrio, {R. C.} and D. Hubbard and S. Gupta and A. Crenshaw and Ramos, {A. H.} and L. Chin and A. Protopopov and Jinghui Zhang and Kim, {T. M.} and I. Perna and Y. Xiao and H. Zhang and G. Ren and N. Sathiamoorthy and Park, {R. W.} and E. Lee and Park, {P. J.} and R. Kucherlapati and Absher, {D. M.} and L. Waite and G. Sherlock and Brooks, {J. D.} and Li, {J. Z.} and J. Xu and Myers, {R. M.} and Laird, {P. W.} and L. Cope and Herman, {J. G.} and H. Shen and Weisenberger, {D. J.} and H. Noushmehr and F. Pan and T. Triche and Berman, {B. P.} and {Van Den Berg}, {D. J.} and J. Buckley and Baylin, {S. B.} and Spellman, {P. T.} and E. Purdom and P. Neuvial and H. Bengtsson and Jakkula, {L. R.} and S. Durinck and J. Han and S. Dorton and H. Marr and Choi, {Y. G.} and V. Wang and Wang, {N. J.} and J. Ngai and Conboy, {J. G.} and B. Parvin and Feiler, {H. S.} and Speed, {T. P.} and Gray, {J. W.} and Socci, {N. D.} and Y. Liang and Taylor, {B. S.} and N. Schultz and L. Borsu and Lash, {A. E.} and C. Brennan and A. Viale and C. Sander and M. Ladanyi and Hoadley, {K. A.} and S. Meng and Y. Du and Y. Shi and L. Li and Turman, {Y. J.} and D. Zang and Helms, {E. B.} and S. Balu and X. Zhou and J. Wu and Topal, {M. D.} and Hayes, {D. N.} and Perou, {C. M.} and Wu, {C. J.} and S. Shukla and A. Sivachenko and R. Jing and Y. Liu and M. Noble and H. Carter and D. Kim and R. Karchin and Korkola, {J. E.} and Heiser, {L. M.} and Cho, {R. J.} and Z. Hu and E. Cerami and A. Olshen and B. Reva and Y. Antipin and R. Shen and P. Mankoo and R. Sheridan and G. Ciriello and Chang, {W. K.} and Bernanke, {J. A.} and D. Haussler and Benz, {C. C.} and Stuart, {J. M.} and Benz, {S. C.} and Sanborn, {J. Z.} and Vaske, {C. J.} and J. Zhu and C. Szeto and Scott, {G. K.} and C. Yau and Wilkerson, {M. D.} and N. Zhang and R. Akbani and Baggerly, {K. A.} and Yung, {W. K.} and Weinstein, {J. N.} and T. Shelton and D. Grimm and M. Hatfield and S. Morris and P. Yena and P. Rhodes and M. Sherman and J. Paulauskis and S. Millis and A. Kahn and Greene, {J. M.} and R. Sfeir and Jensen, {M. A.} and J. Chen and J. Whitmore and S. Alonso and J. Jordan and A. Chu and A. Barker and C. Compton and G. Eley and M. Ferguson and P. Fielding and Gerhard, {D. S.} and R. Myles and C. Schaefer and {Mills Shaw}, {K. R.} and J. Vaught and Vockley, {J. B.} and Good, {P. J.} and Guyer, {M. S.} and B. Ozenberger and J. Peterson and E. Thomson",

note = "Funding Information: Acknowledgements We thank J. Palchik, A. Mirick and Julia Zhang for administrative coordination of TCGA activities. This work was supported by the following grants from the USA National Institutes of Health: U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143840, U24CA143882, U24CA143731, U24CA143835, U24CA143845, U24CA143858, U24CA144025, U24CA143882, U24CA143866, U24CA143867, U24CA143848, U24CA143843 and R21CA135877.",

year = "2011",

month = jun,

day = "30",

doi = "10.1038/nature10166",

language = "English",

volume = "474",

pages = "609--615",

journal = "Nature",

issn = "0028-0836",

number = "7353",

}

Bell, D, Berchuck, A, Birrer, M, Chien, J, Cramer, DW, Dao, F, Dhir, R, Disaia, P, Gabra, H, Glenn, P, Godwin, AK, Gross, J, Hartmann, L, Huang, M, Huntsman, DG, Iacocca, M, Imielinski, M, Kalloger, S, Karlan, BY, Levine, DA, Mills, GB, Morrison, C, Mutch, D, Olvera, N, Orsulic, S, Park, K, Petrelli, N, Rabeno, B, Rader, JS, Sikic, BI, Smith-Mccune, K, Sood, AK, Bowtell, D, Penny, R, Testa, JR, Chang, K, Dinh, HH, Drummond, JA, Fowler, G, Gunaratne, P, Hawes, AC, Kovar, CL, Lewis, LR, Morgan, MB, Newsham, IF, Santibanez, J, Reid, JG, Trevino, LR, Wu, YQ, Wang, M, Muzny, DM, Wheeler, DA, Gibbs, RA, Getz, G, Lawrence, MS, Cibulskis, K, Sivachenko, AY, Sougnez, C, Voet, D, Wilkinson, J, Bloom, T, Ardlie, K, Fennell, T, Baldwin, J, Gabriel, S, Lander, ES, Ding, L, Fulton, RS, Koboldt, DC, McLellan, MD, Wylie, T, Walker, J, O'Laughlin, M, Dooling, DJ, Fulton, L, Abbott, R, Dees, ND, Zhang, Q, Kandoth, C, Wendl, M, Schierding, W, Shen, D, Harris, CC, Schmidt, H, Kalicki, J, Delehaunty, KD, Fronick, CC, Demeter, R, Cook, L, Wallis, JW, Lin, L, Magrini, VJ, Hodges, JS, Eldred, JM, Smith, SM, Pohl, CS, Vandin, F, Raphael, BJ, Weinstock, GM, Mardis, ER, Wilson, RK, Meyerson, M, Winckler, W, Verhaak, RGW, Carter, SL, Mermel, CH, Saksena, G, Nguyen, H, Onofrio, RC, Hubbard, D, Gupta, S, Crenshaw, A, Ramos, AH, Chin, L, Protopopov, A, Zhang, J, Kim, TM, Perna, I, Xiao, Y, Zhang, H, Ren, G, Sathiamoorthy, N, Park, RW, Lee, E, Park, PJ, Kucherlapati, R, Absher, DM, Waite, L, Sherlock, G, Brooks, JD, Li, JZ, Xu, J, Myers, RM, Laird, PW, Cope, L, Herman, JG, Shen, H, Weisenberger, DJ, Noushmehr, H, Pan, F, Triche, T, Berman, BP, Van Den Berg, DJ, Buckley, J, Baylin, SB, Spellman, PT, Purdom, E, Neuvial, P, Bengtsson, H, Jakkula, LR, Durinck, S, Han, J, Dorton, S, Marr, H, Choi, YG, Wang, V, Wang, NJ, Ngai, J, Conboy, JG, Parvin, B, Feiler, HS, Speed, TP, Gray, JW, Socci, ND, Liang, Y, Taylor, BS, Schultz, N, Borsu, L, Lash, AE, Brennan, C, Viale, A, Sander, C, Ladanyi, M, Hoadley, KA, Meng, S, Du, Y, Shi, Y, Li, L, Turman, YJ, Zang, D, Helms, EB, Balu, S, Zhou, X, Wu, J, Topal, MD, Hayes, DN, Perou, CM, Wu, CJ, Shukla, S, Sivachenko, A, Jing, R, Liu, Y, Noble, M, Carter, H, Kim, D, Karchin, R, Korkola, JE, Heiser, LM, Cho, RJ, Hu, Z, Cerami, E, Olshen, A, Reva, B, Antipin, Y, Shen, R, Mankoo, P, Sheridan, R, Ciriello, G, Chang, WK, Bernanke, JA, Haussler, D, Benz, CC, Stuart, JM, Benz, SC, Sanborn, JZ, Vaske, CJ, Zhu, J, Szeto, C, Scott, GK, Yau, C, Wilkerson, MD, Zhang, N, Akbani, R, Baggerly, KA, Yung, WK, Weinstein, JN, Shelton, T, Grimm, D, Hatfield, M, Morris, S, Yena, P, Rhodes, P, Sherman, M, Paulauskis, J, Millis, S, Kahn, A, Greene, JM, Sfeir, R, Jensen, MA, Chen, J, Whitmore, J, Alonso, S, Jordan, J, Chu, A, Barker, A, Compton, C, Eley, G, Ferguson, M, Fielding, P, Gerhard, DS, Myles, R, Schaefer, C, Mills Shaw, KR, Vaught, J, Vockley, JB, Good, PJ, Guyer, MS, Ozenberger, B, Peterson, J & Thomson, E 2011, 'Integrated genomic analyses of ovarian carcinoma', Nature, vol. 474, no. 7353, pp. 609-615. https://doi.org/10.1038/nature10166

TY - JOUR

T1 - Integrated genomic analyses of ovarian carcinoma

AU - Bell, D.

AU - Berchuck, A.

AU - Birrer, M.

AU - Chien, J.

AU - Cramer, D. W.

AU - Dao, F.

AU - Dhir, R.

AU - Disaia, P.

AU - Gabra, H.

AU - Glenn, P.

AU - Godwin, A. K.

AU - Gross, J.

AU - Hartmann, L.

AU - Huang, M.

AU - Huntsman, D. G.

AU - Iacocca, M.

AU - Imielinski, M.

AU - Kalloger, S.

AU - Karlan, B. Y.

AU - Levine, D. A.

AU - Mills, G. B.

AU - Morrison, C.

AU - Mutch, D.

AU - Olvera, N.

AU - Orsulic, S.

AU - Park, K.

AU - Petrelli, N.

AU - Rabeno, B.

AU - Rader, J. S.

AU - Sikic, B. I.

AU - Smith-Mccune, K.

AU - Sood, A. K.

AU - Bowtell, D.

AU - Penny, R.

AU - Testa, J. R.

AU - Chang, K.

AU - Dinh, H. H.

AU - Drummond, J. A.

AU - Fowler, G.

AU - Gunaratne, P.

AU - Hawes, A. C.

AU - Kovar, C. L.

AU - Lewis, L. R.

AU - Morgan, M. B.

AU - Newsham, I. F.

AU - Santibanez, J.

AU - Reid, J. G.

AU - Trevino, L. R.

AU - Wu, Y. Q.

AU - Wang, M.

AU - Muzny, D. M.

AU - Wheeler, D. A.

AU - Gibbs, R. A.

AU - Getz, G.

AU - Lawrence, M. S.

AU - Cibulskis, K.

AU - Sivachenko, A. Y.

AU - Sougnez, C.

AU - Voet, D.

AU - Wilkinson, J.

AU - Bloom, T.

AU - Ardlie, K.

AU - Fennell, T.

AU - Baldwin, J.

AU - Gabriel, S.

AU - Lander, E. S.

AU - Ding, L.

AU - Fulton, R. S.

AU - Koboldt, D. C.

AU - McLellan, M. D.

AU - Wylie, T.

AU - Walker, J.

AU - O'Laughlin, M.

AU - Dooling, D. J.

AU - Fulton, L.

AU - Abbott, R.

AU - Dees, N. D.

AU - Zhang, Q.

AU - Kandoth, C.

AU - Wendl, M.

AU - Schierding, W.

AU - Shen, D.

AU - Harris, C. C.

AU - Schmidt, H.

AU - Kalicki, J.

AU - Delehaunty, K. D.

AU - Fronick, C. C.

AU - Demeter, R.

AU - Cook, L.

AU - Wallis, J. W.

AU - Lin, L.

AU - Magrini, V. J.

AU - Hodges, J. S.

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N1 - Funding Information: Acknowledgements We thank J. Palchik, A. Mirick and Julia Zhang for administrative coordination of TCGA activities. This work was supported by the following grants from the USA National Institutes of Health: U54HG003067, U54HG003079, U54HG003273, U24CA126543, U24CA126544, U24CA126546, U24CA126551, U24CA126554, U24CA126561, U24CA126563, U24CA143840, U24CA143882, U24CA143731, U24CA143835, U24CA143845, U24CA143858, U24CA144025, U24CA143882, U24CA143866, U24CA143867, U24CA143848, U24CA143843 and R21CA135877.

PY - 2011/6/30

Y1 - 2011/6/30

N2 - A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

AB - A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

UR - http://www.scopus.com/inward/record.url?scp=79959838081&partnerID=8YFLogxK

U2 - 10.1038/nature10166

DO - 10.1038/nature10166

M3 - Article

AN - SCOPUS:79959838081

SN - 0028-0836

VL - 474

SP - 609

EP - 615

JO - Nature

JF - Nature

IS - 7353

ER -

Integrated genomic analyses of ovarian carcinoma

Abstract

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