Comprehensive molecular characterization of urothelial bladder carcinoma

被引：2263

作者：

Weinstein, John N. ^{[1
]}

Akbani, Rehan ^{[1
]}

Broom, Bradley M. ^{[1
]}

Wang, Wenyi ^{[1
]}

Verhaak, Roeland G. W. ^{[1
]}

McConkey, David ^{[3
]}

Lerner, Seth ^{[4
]}

Morgan, Margaret ^{[5
]}

Creighton, Chad J. ^{[7
]}

Smith, Carolyn ^{[8
]}

Kwiatkowski, David J. ^{[9
,10
,11
]}

Cherniack, Andrew D.

Kim, Jaegil

Pedamallu, Chandra Sekhar

Noble, Michael S.

Al-Ahmadie, Hikmat A.

Reuter, Victor E.

Rosenberg, Jonathan E.

Bajorin, Dean F.

Bochner, Bernard H.

Solit, David B.

Koppie, Theresa ^{[14
]}

Robinson, Brian

Gordenin, Dmitry A. ^{[15
]}

Fargo, David ^{[15
]}

Klimczak, Leszek J. ^{[15
]}

Roberts, Steven A. ^{[15
]}

Au, Jessie ^{[16
]}

Laird, Peter W.

Hinoue, Toshinori

Schultz, Nikolaus ^{[18
]}

Ramirez, Ricardo ^{[18
]}

Hansel, Donna ^{[19
]}

Hoadley, Katherine A. ^{[20
]}

Kim, William Y.

Damrauer, Jeffrey S.

Baylin, Stephen B. ^{[22
]}

Mungall, Andrew J. ^{[26
]}

Robertson, A. Gordon

Chu, Andy ^{[26
]}

Kwiatkowski, David J. ^{[9
,10
,11
]}

Sougnez, Carrie

Cibulskis, Kristian ^{[9
]}

Lichtenstein, Lee ^{[9
]}

Sivachenko, Andrey ^{[9
]}

Stewart, Chip ^{[9
]}

Lawrence, Michael S. ^{[9
]}

Getz, Gad ^{[9
]}

Lander, Eric ^{[9
]}

Gabriel, Stacey B. ^{[9
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

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

[3] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[4] Baylor Coll Med, Scott Dept Urol, Houston, TX 77030 USA

[5] Baylor Coll Med, TCRB, Houston, TX 77030 USA

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

[7] Baylor Coll Med, Human Genome Sequencing Ctr, Dan L Duncan Canc Ctr, Houston, TX 77030 USA

[8] Baylor Coll Med, Houston, TX 77030 USA

[9] Eli & Edythe L Broad Inst Massachusetts Inst Tech, Cambridge, MA 02142 USA

[10] Brigham & Womens Hosp, Boston, MA 02115 USA

[11] Harvard Univ, Sch Med, Boston, MA 02115 USA

[12] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[13] Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA

[14] Oregon Hlth & Sci Univ, Dept Urol, Portland, OR 97239 USA

[15] NIEHS, Res Triangle Pk, NC 27709 USA

[16] OptimumTherapeutics LLC, San Diego, CA 92121 USA

[17] Univ So Calif, Epigenome Ctr, Los Angeles, CA 90033 USA

[18] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA

[19] UCSD Dept Pathol, La Jolla, CA 92093 USA

[20] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[21] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[22] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Canc Biol Div, Baltimore, MD 21231 USA

[23] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA

[24] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[25] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02215 USA

[26] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada

[27] Univ N Carolina, Dept Internal Med, Div Med Oncol, Chapel Hill, NC 27599 USA

[28] Univ N Carolina, Res Comp Ctr, Chapel Hill, NC 27599 USA

[29] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA

[30] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA

[31] Univ N Carolina, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

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

[33] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

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

[35] Childrens Hosp, Informat Program, Boston, MA 02115 USA

[36] Univ Texas MD Anderson Canc Ctr, Dept Genom Med, Inst Appl Canc Sci, Houston, TX 77030 USA

[37] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[38] Inst Syst Biol, Seattle, WA 98109 USA

[39] Buck Inst Res Aging, Novato, CA 94945 USA

[40] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA

[41] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[42] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA

[43] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA

[44] Ohio State Univ, Columbus, OH 43210 USA

[45] Baylor Coll Med, Dept Pathol, Houston, TX 77030 USA

[46] Analyt Biol Serv Inc, Wilmington, DE 19801 USA

[47] Cleveland Clin Fdn, Cleveland, OH 44195 USA

[48] Georgia Regents Univ, Canc Ctr, Augusta, GA 30912 USA

[49] Christiana Care, Helen F Graham Canc Ctr, Newark, DE 19713 USA

[50] Int Genom Consortium, Phoenix, AZ 85004 USA

来源：

NATURE | 2014年 / 507卷 / 7492期

基金：

美国国家卫生研究院;

关键词：

GENE FUSIONS; CANCER; MUTATIONS; GENOMES; KINASE; FGFR;

D O I：

10.1038/nature12965

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：

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomasto provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

引用

页码：315 / 322

页数：8

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