Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy

被引：573

作者：

Barretina, Jordi ^{[2
,3
,4
]}

Taylor, Barry S. ^{[1
,5
]}

Banerji, Shantanu ^{[2
,3
,4
]}

Ramos, Alexis H. ^{[2
,3
,4
]}

Lagos-Quintana, Mariana ^{[6
]}

DeCarolis, Penelope L. ^{[6
]}

Shah, Kinjal ^{[2
,4
]}

Socci, Nicholas D. ^{[1
]}

Weir, Barbara A. ^{[2
,3
,4
]}

Ho, Alan ^{[7
]}

Chiang, Derek Y. ^{[2
,3
,4
]}

Reva, Boris ^{[1
]}

Mermel, Craig H. ^{[2
,3
,4
]}

Getz, Gad ^{[4
]}

Antipin, Yevgenyi ^{[1
]}

Beroukhim, Rameen ^{[2
,3
,4
]}

Major, John E. ^{[1
]}

Hatton, Charles ^{[2
,3
]}

Nicoletti, Richard ^{[2
,3
]}

Hanna, Megan ^{[2
,3
]}

Sharpe, Ted ^{[4
]}

Fennell, Tim J. ^{[4
]}

Cibulskis, Kristian ^{[4
]}

Onofrio, Robert C. ^{[4
]}

Saito, Tsuyoshi ^{[8
,9
]}

Shukla, Neerav ^{[8
,9
]}

Lau, Christopher ^{[8
,9
]}

Nelander, Sven ^{[1
]}

Silver, Serena J. ^{[4
]}

Sougnez, Carrie ^{[4
]}

Viale, Agnes ^{[10
]}

Winckler, Wendy ^{[2
,4
]}

Maki, Robert G.

Garraway, Levi A. ^{[2
,3
,4
]}

Lash, Alex ^{[1
]}

Greulich, Heidi ^{[1
,2
,3
]}

Root, David E. ^{[4
]}

Sellers, William R. ^{[11
]}

Schwartz, Gary K. ^{[7
]}

Antonescu, Cristina R.

Lander, Eric S. ^{[4
]}

Varmus, Harold E. ^{[12
]}

Ladanyi, Marc ^{[8
,9
]}

Sander, Chris ^{[1
]}

Meyerson, Matthew ^{[2
,3
,4
,13
]}

Singer, Samuel ^{[6
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10021 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA USA

[5] Cornell Univ, Dept Physiol & Biophys, Weill Med Coll, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Surg, Sarcoma Biol Lab, Sarcoma Dis Management Program, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Lab New Drug Dev, Dept Med, New York, NY 10021 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[10] Sloan Kettering Inst, Genom Core Lab, New York, NY USA

[11] Novartis Inst Biomed Res, Cambridge, MA USA

[12] Mem Sloan Kettering Canc Ctr, Program Canc Biol & Genet, New York, NY 10021 USA

[13] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

来源：

NATURE GENETICS | 2010年 / 42卷 / 08期

关键词：

GASTROINTESTINAL STROMAL TUMORS; HUMAN CANCER GENES; DEDIFFERENTIATED LIPOSARCOMA; ANTAGONIST NUTLIN-3A; PIK3CA GENE; MUTATIONS; CELLS; PATHWAY; P53; CENSUS;

D O I：

10.1038/ng.619

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States(1), show remarkable histologic diversity, with more than 50 recognized subtypes(2). However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.

引用

页码：715 / U103

页数：9

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