An integrative approach identified genes associated with drug response in gastric cancer.
Gastric cancer (GC) is the second leading cause of global cancer mortality worldwide. However, the molecular mechanism underlying its carcinogenesis and drug resistance is not well understood. To identify novel functionally important genes that were differentially expressed due to combinations of genetic and epigenetic changes, we analyzed datasets containing genome-wide mRNA expression, DNA copy number alterations and DNA methylation status from 154 primary GC samples and 47 matched non-neoplastic mucosa tissues from Asian patients. We used concepts of 'within' and 'between' statistical analysis to compare the difference between tumors and controls within each platform, and assessed the correlations between platforms. This 'multi-regulated gene (MRG)' analysis identified 126 differentially expressed genes that underwent a combination of copy number and DNA methylation changes. Most genes were located at genomic loci associated with GC. Statistical enrichment analysis showed that MRGs were enriched for cancer, GC and drug response. We analysed several MRGs that previously had not been associated with GC. Knockdown of DDX27, TH1L or IDH3G sensitized cells to epirubicin or cisplatin, and knockdown of RAI14 reduced cell proliferation. Further studies showed that overexpression of DDX27 reduced epirubicin-induced DNA damage and apoptosis. Levels of DDX27 mRNA and protein were increased in early-stage gastric tumors, and may be a potential diagnostic and prognostic marker for GC. In summary, we used an integrative bioinformatics strategy to identify novel genes that are altered in GC and regulate resistance of GC cells to drugs in vitro.
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Jin
J
Zhou
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
Wei-Peng
WP
Yong
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Chui Sun
CS
Yap
Centre for Quantitative Medicine, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore;
Aadhitthya
A
Vijayaraghavan
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Rohit Anthony
RA
Sinha
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Brijesh Kumar
BK
Singh
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
Sam
S
Xiu
Experimental Therapeutics Centre, Singapore, Singapore.
Sravanthy
S
Manesh
Experimental Therapeutics Centre, Singapore, Singapore.
Anna
A
Ngo
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Andrea
A
Lim
Laboratory of Computational Biology, Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.
Carolyn
C
Ang
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
Chen
C
Xie
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
Foong Ying
FY
Wong
Genome Institute of Singapore, Singapore.
Suling J
SJ
Lin
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
Wei Keat
WK
Wan
Department of Medical Oncology, National Cancer Centre, Singapore, Singapore, Department of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Iain Beehuat
IB
Tan
Experimental Therapeutics Centre, Singapore, Singapore.
Horst
H
Flotow
Laboratory of Genomic Oncology, Cancer and Stem Cell Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, Cellular and Molecular Research, National Cancer Centre, Singapore, Singapore, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Genome Institute of Singapore, Singapore.
Patrick
P
Tan
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
Kiat-Hon
KH
Lim
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA, paul.yen@duke-nus.edu.sg.
Paul Michael
PM
Yen
Centre for Quantitative Medicine, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore; Laboratory of Computational Biology, Cancer and Stem Cell Biology Program, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore, Department of Medical Oncology, National Cancer Centre, Singapore, Singapore, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
Liang Kee
LK
Goh
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D030561:Databases, Nucleic Acid; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015251:Epirubicin / Q000494:pharmacology; D005753:Gastric Mucosa / Q000166:cytology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics; D011379:Prognosis; D034622:RNA Interference; D034741:RNA, Small Interfering; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D003598:Cytoskeletal Proteins; C468783:H2AX protein, human; D006657:Histones; C104144:NELL1 protein, human; D009419:Nerve Tissue Proteins; C428450:RAI14 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; C118437:negative elongation factor; D015251:Epirubicin; C000598634:DDX27 protein, human; D053487:DEAD-box RNA Helicases; D002945:Cisplatin