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.
Duke-NUS Graduate Medical School, Singapore.
Chia Huey
CH
Ooi
Tatiana
T
Ivanova
Jeanie
J
Wu
Minghui
M
Lee
Iain Beehuat
IB
Tan
Jiong
J
Tao
Lindsay
L
Ward
Jun Hao
JH
Koo
Veena
V
Gopalakrishnan
Yansong
Y
Zhu
Lai Ling
LL
Cheng
Julian
J
Lee
Sun Young
SY
Rha
Hyun Cheol
HC
Chung
Kumaresan
K
Ganesan
Jimmy
J
So
Khee Chee
KC
Soo
Dennis
D
Lim
Weng Hoong
WH
Chan
Wai Keong
WK
Wong
David
D
Bowtell
Khay Guan
KG
Yeoh
Heike
H
Grabsch
Alex
A
Boussioutas
Patrick
P
Tan
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