Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.
Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. 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.
Barretina
Jordi
J
Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA.
Taylor
Barry S
BS
Banerji
Shantanu
S
Ramos
Alexis H
AH
Lagos-Quintana
Mariana
M
Decarolis
Penelope L
PL
Shah
Kinjal
K
Socci
Nicholas D
ND
Weir
Barbara A
BA
Ho
Alan
A
Chiang
Derek Y
DY
Reva
Boris
B
Mermel
Craig H
CH
Getz
Gad
G
Antipin
Yevgenyi
Y
Beroukhim
Rameen
R
Major
John E
JE
Hatton
Charles
C
Nicoletti
Richard
R
Hanna
Megan
M
Sharpe
Ted
T
Fennell
Tim J
TJ
Cibulskis
Kristian
K
Onofrio
Robert C
RC
Saito
Tsuyoshi
T
Shukla
Neerav
N
Lau
Christopher
C
Nelander
Sven
S
Silver
Serena J
SJ
Sougnez
Carrie
C
Viale
Agnes
A
Winckler
Wendy
W
Maki
Robert G
RG
Garraway
Levi A
LA
Lash
Alex
A
Greulich
Heidi
H
Root
David E
DE
Sellers
William R
WR
Schwartz
Gary K
GK
Antonescu
Cristina R
CR
Lander
Eric S
ES
Varmus
Harold E
HE
Ladanyi
Marc
M
Sander
Chris
C
Meyerson
Matthew
M
Singer
Samuel
S
D000328:Adult; D000368:Aged; D005260:Female; D016147:Genes, Tumor Suppressor; D016678:Genome; D051677:Histiocytoma, Malignant Fibrous / Q000235:genetics*; D006801:Humans; D008080:Liposarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology