Oncogenic pathway combinations predict clinical prognosis in gastric cancer.
Many solid cancers are known to exhibit a high degree of heterogeneity in their deregulation of different oncogenic pathways. We sought to identify major oncogenic pathways in gastric cancer (GC) with significant relationships to patient survival. Using gene expression signatures, we devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers, the second highest cause of global cancer mortality. We identified three oncogenic pathways (proliferation/stem cell, NF-kappaB, and Wnt/beta-catenin) deregulated in the majority (>70%) of gastric cancers. We functionally validated these pathway predictions in a panel of gastric cancer cell lines. Patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior. Individual GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Predicting pathway activity by expression signatures thus permits the study of multiple cancer-related pathways interacting simultaneously in primary cancers, at a scale not currently achievable by other platforms.
Ooi
Chia Huey
CH
Duke-NUS Graduate Medical School, Singapore.
Ivanova
Tatiana
T
Wu
Jeanie
J
Lee
Minghui
M
Tan
Iain Beehuat
IB
Tao
Jiong
J
Ward
Lindsay
L
Koo
Jun Hao
JH
Gopalakrishnan
Veena
V
Zhu
Yansong
Y
Cheng
Lai Ling
LL
Lee
Julian
J
Rha
Sun Young
SY
Chung
Hyun Cheol
HC
Ganesan
Kumaresan
K
So
Jimmy
J
Soo
Khee Chee
KC
Lim
Dennis
D
Chan
Weng Hoong
WH
Wong
Wai Keong
WK
Bowtell
David
D
Yeoh
Khay Guan
KG
Grabsch
Heike
H
Boussioutas
Alex
A
Tan
Patrick
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult