Integrated genomic analyses of ovarian carcinoma

被引：5984

作者：

Bell, D. ^{[1
]}

Berchuck, A. ^{[2
,3
]}

Birrer, M. ^{[4
,5
]}

Chien, J. ^{[6
]}

Cramer, D. W. ^{[7
]}

Dao, F.

Dhir, R. ^{[9
]}

DiSaia, P. ^{[10
]}

Gabra, H. ^{[11
]}

Glenn, P. ^{[12
]}

Godwin, A. K. ^{[13
]}

Gross, J. ^{[14
]}

Hartmann, L. ^{[15
]}

Huang, M. ^{[16
]}

Huntsman, D. G. ^{[17
]}

Iacocca, M. ^{[18
]}

Imielinski, M. ^{[5
]}

Kalloger, S. ^{[17
]}

Karlan, B. Y. ^{[14
,19
]}

Levine, D. A. ^{[8
]}

Mills, G. B. ^{[20
]}

Morrison, C. ^{[21
,22
]}

Mutch, D. ^{[23
]}

Olvera, N.

Orsulic, S. ^{[14
]}

Park, K. ^{[24
]}

Petrelli, N. ^{[25
]}

Rabeno, B. ^{[18
]}

Rader, J. S. ^{[26
]}

Sikic, B. I. ^{[27
]}

Smith-McCune, K. ^{[12
]}

Sood, A. K. ^{[28
,29
]}

Bowtell, D. ^{[30
]}

Penny, R. ^{[31
]}

Testa, J. R. ^{[32
]}

Chang, K. ^{[33
]}

Dinh, H. H. ^{[33
]}

Drummond, J. A. ^{[33
]}

Fowler, G. ^{[33
]}

Gunaratne, P. ^{[33
]}

Hawes, A. C. ^{[33
]}

Kovar, C. L. ^{[33
]}

Lewis, L. R. ^{[33
]}

Morgan, M. B. ^{[33
]}

Newsham, I. F. ^{[33
]}

Santibanez, J. ^{[33
]}

Reid, J. G. ^{[33
]}

Trevino, L. R. ^{[33
]}

Wu, Y. -Q. ^{[33
]}

Wang, M. ^{[33
]}

机构：

[1] Mayo Clin, Div Anat Pathol, Rochester, MN 55905 USA

[2] Duke Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Med Ctr, Durham, NC 27708 USA

[3] Duke Univ, Duke Inst Genome Sci & Policy, Med Ctr, Durham, NC 27708 USA

[4] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Boston, MA 02114 USA

[6] Mayo Clin, Div Expt Pathol, Rochester, MN 55905 USA

[7] Brigham & Womens Hosp, Dept Obstet & Gynecol, Epidemiol Ctr, Boston, MA 02115 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[9] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15213 USA

[10] Univ Calif Irvine, Gynecol Oncol Grp, Irvine, CA 92697 USA

[11] Univ London Imperial Coll Sci Technol & Med, Dept Surg & Canc, Ovarian Canc Act Res Ctr, London W12 0NN, England

[12] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Serv, San Francisco, CA 94143 USA

[13] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA

[14] Univ Calif Los Angeles, Canc Res Inst, Samuel Oschin Comprehens Canc Inst, Cedars Sinai Med Ctr,Geffen Sch Med, Los Angeles, CA 90048 USA

[15] Mayo Clin, Div Med Oncol, Rochester, MN 55905 USA

[16] Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA

[17] British Columbia Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC V5Z 1G1, Canada

[18] Christiana Care Hlth Syst, Dept Pathol, Newark, DE 19718 USA

[19] Univ Calif Los Angeles, Dept Obstet & Gynecol, Cedars Sinai Med Ctr, Geffen Sch Med, Los Angeles, CA 90048 USA

[20] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[21] Roswell Pk Canc Inst, Dept Pathol & Lab Med, Buffalo, NY 14263 USA

[22] Roswell Pk Canc Inst, Div Mol Pathol, Buffalo, NY 14263 USA

[23] Washington Univ, Div Gynecol Oncol, Dept Obstet & Gynecol, Sch Med St Louis, St Louis, MO 63110 USA

[24] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[25] Helen F Graham Canc Ctr Christina Care, Dept Surg, Newark, DE 19713 USA

[26] Med Coll Wisconsin, Human & Mol Genet Ctr, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA

[27] Stanford Univ, Dept Med, Div Oncol, Sch Med, Palo Alto, CA 94304 USA

[28] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77230 USA

[29] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNA, Houston, TX 77230 USA

[30] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic 8006, Australia

[31] Internat Genom Consortium, Phoenix, AZ 85004 USA

[32] Fox Chase Canc Ctr, Canc Biol Program, Philadelphia, PA 19111 USA

[33] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[34] MIT, Eli & Edythe L Broad Inst, Canc Genome Project, Cambridge, MA 02142 USA

[35] MIT, Eli & Edythe L Broad Inst, Med Resequencing Project, Cambridge, MA 02142 USA

[36] Harvard Univ, Cambridge, MA 02142 USA

[37] MIT, Dept Biol, Cambridge, MA 02142 USA

[38] Harvard Univ, Dept Syst Biol, Boston, MA 02115 USA

[39] Washington Univ, Sch Med St Louis, Genome Ctr, Dept Genet, St Louis, MO 63108 USA

[40] Brown Univ, Dept Comp Sci, Providence, RI 02912 USA

[41] Brown Univ, Ctr Computat Mol Biol, Providence, RI 02912 USA

[42] Washington Univ, Siteman Canc Ctr, Sch Med St Louis, St Louis, MO 63108 USA

[43] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[44] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[45] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Dept Med Oncol, Boston, MA 02115 USA

[46] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA

[47] Harvard Univ, Ctr Biomed Informat, Sch Med, Boston, MA 02115 USA

[48] Partners Ctr Personalized Genet Med, Cambridge, MA 02139 USA

[49] Harvard Univ, Dept Genet, Sch Med, Boston, MA 02115 USA

[50] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

来源：

NATURE | 2011年 / 474卷 / 7353期

基金：

美国国家卫生研究院;

关键词：

HIGH-THROUGHPUT ANNOTATION; SOMATIC MUTATIONS; DRIVER MUTATIONS; HYBRID SELECTION; MUTANT-CELLS; COPY-NUMBER; CANCER; BRCA1; BREAST; HYPERMETHYLATION;

D O I：

10.1038/nature10166

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：609 / 615

页数：7

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