title: Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer.
abstract: OBJECTIVE
  Cisplatin is a widely used gastric cancer (GC) chemotherapy; however, genetic factors regulating GC responses to cisplatin remain obscure. Identifying genes regulating cisplatin resistance could aid clinicians in tailoring treatments, by distinguishing cisplatin sensitive patients from those who might benefit from alternative platinum therapies, and highlight novel targeted strategies for overcoming cisplatin resistance. Here integrated epigenomics is applied to identify genes associated with GC cisplatin resistance.
  
  
  METHODS
  20 GC cell lines were subjected to gene expression profiling, DNA methylation profiling and drug response assays. The molecular data were integrated to identify genes highly expressed and unmethylated specifically in cisplatin-resistant lines. Candidate genes were functionally tested by several in vitro and in vivo assays. Clinical impact of candidate genes was also assessed in a cohort of 197 GC patients.
  
  
  RESULTS
  Epigenomic analysis identified bone morphogenetic protein 4 (BMP4) as an epigenetically regulated gene highly expressed in cisplatin-resistant lines. Functional assays confirmed that BMP4 is necessary and sufficient for the expression of several prooncogenic traits, likely mediated through stimulation of the epithelial-mesenchymal transition. In primary tumours, BMP4 promoter methylation levels were inversely correlated with BMP4 expression, and patients with high BMP4-expressing tumours exhibited significantly worse prognosis. Therapeutically, targeted genetic inhibition of BMP4 caused significant sensitisation of GC cells to cisplatin. Notably, BMP4-expressing GCs also did not exhibit cross resistance to oxaliplatin.
  
  
  CONCLUSIONS
  BMP4 epigenetic and expression status may represent promising biomarkers for GC cisplatin resistance. Targeting BMP4 may sensitise GC cells to cisplatin. Oxaliplatin, a clinically acceptable cisplatin alternative, may represent a potential therapeutic option for BMP4-positive GCs.
authors.affiliation: Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore 169610, Singapore. gmstanp@duke-nus.edu.sg
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ivanova
authors.forename: Hermioni
authors.initials: H
authors.lastname: Zouridis
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Wu
authors.forename: Lai Ling
authors.initials: LL
authors.lastname: Cheng
authors.forename: Iain Beehuat
authors.initials: IB
authors.lastname: Tan
authors.forename: Veena
authors.initials: V
authors.lastname: Gopalakrishnan
authors.forename: Chia Huey
authors.initials: CH
authors.lastname: Ooi
authors.forename: Julian
authors.initials: J
authors.lastname: Lee
authors.forename: Luo
authors.initials: L
authors.lastname: Qin
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Minghui
authors.initials: M
authors.lastname: Lee
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Dan
authors.initials: D
authors.lastname: Huang
authors.forename: Natalia
authors.initials: N
authors.lastname: Liem
authors.forename: Khay Guan
authors.initials: KG
authors.lastname: Yeoh
authors.forename: Wei Peng
authors.initials: WP
authors.lastname: Yong
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; C525809:BMP4 protein, human; D014408:Biomarkers, Tumor; D055415:Bone Morphogenetic Protein 4; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin