A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets.
OBJECTIVE
Gastric cancer is a major gastrointestinal malignancy for which targeted therapies are emerging as treatment options. This study sought to identify the most prevalent molecular targets in gastric cancer and to elucidate systematic patterns of exclusivity and co-occurrence among these targets, through comprehensive genomic analysis of a large panel of gastric cancers.


METHODS
Using high-resolution single nucleotide polymorphism arrays, copy number alterations were profiled in a panel of 233 gastric cancers (193 primary tumours, 40 cell lines) and 98 primary matched gastric non-malignant samples. For selected alterations, their impact on gene expression and clinical outcome were evaluated.


RESULTS
22 recurrent focal alterations (13 amplifications and nine deletions) were identified. These included both known targets (FGFR2, ERBB2) and also novel genes in gastric cancer (KLF5, GATA6). Receptor tyrosine kinase (RTK)/RAS alterations were found to be frequent in gastric cancer. This study also demonstrates, for the first time, that these alterations occur in a mutually exclusive fashion, with KRAS gene amplifications highlighting a clinically relevant but previously underappreciated gastric cancer subgroup. FGFR2-amplified gastric cancers were also shown to be sensitive to dovitinib, an orally bioavailable FGFR/VEGFR targeting agent, potentially representing a subtype-specific therapy for FGFR2-amplified gastric cancers.


CONCLUSIONS
The study demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies.
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore. gmstanp@duke-nus.edu.sg
Niantao
N
Deng
Liang Kee
LK
Goh
Hannah
H
Wang
Kakoli
K
Das
Jiong
J
Tao
Iain Beehuat
IB
Tan
Shenli
S
Zhang
Minghui
M
Lee
Jeanie
J
Wu
Kiat Hon
KH
Lim
Zhengdeng
Z
Lei
Glenn
G
Goh
Qing-Yan
QY
Lim
Angie Lay-Keng
AL
Tan
Dianne Yu
DY
Sin Poh
Sudep
S
Riahi
Sandra
S
Bell
Michael M
MM
Shi
Ronald
R
Linnartz
Feng
F
Zhu
Khay Guan
KG
Yeoh
Han Chong
HC
Toh
Wei Peng
WP
Yong
Hyun Cheol
HC
Cheong
Sun Young
SY
Rha
Alex
A
Boussioutas
Heike
H
Grabsch
Steve
S
Rozen
Patrick
P
Tan
D000970:Antineoplastic Agents / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D005784:Gene Amplification; D017353:Gene Deletion; D005819:Genetic Markers; D058990:Molecular Targeted Therapy; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018631:ras Proteins / Q000235:genetics
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005819:Genetic Markers; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D018631:ras Proteins; C117307:KRAS protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C496353:FGFR2 protein, human; C491743:MET protein, human