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Integrated epigenomics identifies BMP4 as a modulator of cisplatin sensitivity in gastric cancer
  1. Tatiana Ivanova1,
  2. Hermioni Zouridis1,
  3. Yonghui Wu2,
  4. Lai Ling Cheng1,3,
  5. Iain Beehuat Tan4,
  6. Veena Gopalakrishnan1,
  7. Chia Huey Ooi1,
  8. Julian Lee2,
  9. Luo Qin1,
  10. Jeanie Wu2,
  11. Minghui Lee2,
  12. Sun Young Rha5,
  13. Dan Huang6,
  14. Natalia Liem7,
  15. Khay Guan Yeoh8,
  16. Wei Peng Yong9,
  17. Bin Tean Teh10,
  18. Patrick Tan1,7,11
  1. 1Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
  2. 2Cellular and Molecular Research, National Cancer Centre, Singapore
  3. 3Singapore-MIT Alliance, National University of Singapore, Singapore
  4. 4Division of Medical Oncology, National Cancer Centre, Singapore
  5. 5Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
  6. 6Laboratory of Cancer Genetics, Van Andel Research Institute, Michigan, USA
  7. 7Cancer Science Institute of Singapore, National University of Singapore, Singapore
  8. 8Department of Medicine, National University Hospital Singapore, Singapore
  9. 9National Cancer Institute, National University Hospital Singapore, Singapore
  10. 10NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore
  11. 11Genome Institute of Singapore, Singapore
  1. Correspondence to Dr Patrick Tan, Duke-NUS Graduate Medical School, 11 Hospital Drive, Singapore 169610, Singapore; gmstanp{at}duke-nus.edu.sg

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.

Design 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.

  • Gastric cancer
  • cisplatin
  • BMP4
  • DNA methylation
  • carcinogenesis
  • gastric pre-cancer
  • gastric carcinoma
  • gene expression
  • gene mutation

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Footnotes

  • Funding This work was supported by grant NMRC TCR/001/2007, a Duke-NUS core grant, and a CSIS core grant (PT). We acknowledge the assistance of the Van Andel Research Institute animal facility. Microarray profiling was performed at the Duke-NUS Genome Biology Facility.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was approved by the Institutional Research Ethics Review Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The methylation data have been uploaded onto the Gene Expression Omnibus under accession number GSE29499.

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