SETD2 histone modifier loss in aggressive GI stromal tumours. Issue 12 (3rd September 2015)

• Record Type: Journal Article
• Authors: Huang, Kie Kyon; McPherson, John R; Tay, Su Ting; Das, Kakoli; Tan, Iain Beehuat; Ng, Cedric Chuan Young; Chia, Na-Yu; Zhang, Shen Li; Myint, Swe Swe; Hu, Longyu; Rajasegaran, Vikneswari; Huang, Dachuan; Loh, Jia Liang; Gan, Anna; Sairi, Alisa Noor Hidayah; Sam, Xin Xiu; Dominguez, Lourdes Trinidad; Lee, Minghui; Soo, Khee Chee; Ooi, London Lucien Peng Jin; Ong, Hock Soo; Chung, Alexander; Chow, Pierce Kah-Hoe; Wong, Wai Keong; Selvarajan, Sathiyamoorthy; Ong, Choon Kiat; Lim, Kiat Hon; Nandi, Tannistha; Rozen, Steve; Teh, Bin Tean; Quek, Richard; Tan, Patrick;
• Is Part Of: Gut. Volume 65:Issue 12(2016)
• Page Start: 1960
• Page End: 1972
• Publication Date: 2015-09-03
• Subjects: GENE MUTATION -- GASTROINTESTINAL CANCER; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2015-309482
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.