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SETD2 histone modifier loss in aggressive GI stromal tumours
  1. Kie Kyon Huang1,2,
  2. John R McPherson2,
  3. Su Ting Tay2,
  4. Kakoli Das2,
  5. Iain Beehuat Tan3,4,
  6. Cedric Chuan Young Ng5,
  7. Na-Yu Chia2,
  8. Shen Li Zhang2,
  9. Swe Swe Myint5,
  10. Longyu Hu1,2,
  11. Vikneswari Rajasegaran5,
  12. Dachuan Huang5,
  13. Jia Liang Loh5,
  14. Anna Gan5,
  15. Alisa Noor Hidayah Sairi3,
  16. Xin Xiu Sam6,
  17. Lourdes Trinidad Dominguez3,
  18. Minghui Lee2,
  19. Khee Chee Soo7,
  20. London Lucien Peng Jin Ooi8,
  21. Hock Soo Ong9,
  22. Alexander Chung8,
  23. Pierce Kah-Hoe Chow7,10,11,
  24. Wai Keong Wong9,
  25. Sathiyamoorthy Selvarajan6,
  26. Choon Kiat Ong5,
  27. Kiat Hon Lim6,
  28. Tannistha Nandi4,
  29. Steve Rozen2,
  30. Bin Tean Teh1,2,5,
  31. Richard Quek3,
  32. Patrick Tan1,2,4
  1. 1Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, Singapore, Singapore
  2. 2Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore
  3. 3Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
  4. 4Genome Institute of Singapore, Singapore, Singapore
  5. 5Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
  6. 6Department of Pathology, Singapore General Hospital, 11 Hospital Drive, Singapore, Singapore
  7. 7Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, Singapore
  8. 8Department of Hepatopancreaticobiliary & Transplant Surgery, Singapore General Hospital, Singapore, Singapore
  9. 9Department of Upper GI & Bariatric Surgery, Singapore General Hospital, Singapore, Singapore
  10. 10Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore, Singapore
  11. 11Program in Translational and Clinical Liver Research, National Cancer Center Singapore, 11 Hospital Drive, Singapore, Singapore
  1. Correspondence to Dr Patrick Tan, Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore; gmstanp{at} or Dr Richard Quek, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore; dmorqhh{at}


Background GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients.

Objectives We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers.

Designs Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined.

Results High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10−5). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10−5).

Conclusions Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.


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  • SR, BTT, RQ and PT contributed equally.

  • Contributors KKH, IBT, SR, BTT, RQ, PT: conception and design of the study; drafting and revision of the manuscript; approval of the final version of the manuscript. KKH, JRM, STT, KD, CCYN, N-YC, SLZ, SSM, LH, VR, DH, JLL, AG, ANHS, XXS, LTD, ML, KCS, LLPJO, HSO, AC, PK-HC, WKW, SS, CKO, KHL, TN: generation, collection, assembly of data. KKH, JRM, IBT, SR, BTT, RQ, PT: analysis and interpretation of data.

  • Funding This work was supported by grants from National Medical Research Council (NMRC/TCR/009-NUHS/2013 and NMRC/STAR/0006/2009), National Cancer Centre Research Fund (NCCRF-Y2011-T2-101), National University Health System Center Grant (NMRC/CG/012/2013), Duke-NUS Graduate Medical School Singapore, Cancer Science Institute of Singapore, the Lee Foundation, the Verdant Foundation, Hong Kong and Tanoto Foundation, Indonesia. A portion of this research was supported by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. These sponsors played no role in the study design or the collection, analysis, and interpretation of data.

  • Competing interests These authors disclose the following. RQ has received honoraria from Novartis. PK-HC has received travel and accommodation expenses from Novartis. The remaining authors disclose no conflicts.

  • Patient consent Obtained.

  • Ethics approval Singapore Health Services (SingHealth) Institutional Review Board (application 2010/347/B).

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