Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer.
Gastric cancer is a heterogeneous disease with multiple environmental etiologies and alternative pathways of carcinogenesis. Beyond mutations in TP53, alterations in other genes or pathways account for only small subsets of the disease. We performed exome sequencing of 22 gastric cancer samples and identified previously unreported mutated genes and pathway alterations; in particular, we found genes involved in chromatin modification to be commonly mutated. A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS). The mutation spectrum for ARID1A differs between molecular subtypes of gastric cancer, and mutation prevalence is negatively associated with mutations in TP53. Clinically, ARID1A alterations were associated with better prognosis in a stage-independent manner. These results reveal the genomic landscape, and highlight the importance of chromatin remodeling, in the molecular taxonomy of gastric cancer.
Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla, California, USA.
Kai
K
Wang
Junsuo
J
Kan
Siu Tsan
ST
Yuen
Stephanie T
ST
Shi
Kent Man
KM
Chu
Simon
S
Law
Tsun Leung
TL
Chan
Zhengyan
Z
Kan
Annie S Y
AS
Chan
Wai Yin
WY
Tsui
Siu Po
SP
Lee
Siu Lun
SL
Ho
Anthony K W
AK
Chan
Grace H W
GH
Cheng
Peter C
PC
Roberts
Paul A
PA
Rejto
Neil W
NW
Gibson
David J
DJ
Pocalyko
Mao
M
Mao
Jiangchun
J
Xu
Suet Yi
SY
Leung
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D052138:Genes, Neoplasm; D056726:Genetic Association Studies; D006801:Humans; D007365:Intercellular Junctions; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
C112476:ARID1A protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors