SETD2 histone modifier loss in aggressive GI stromal tumours
SETD2 histone modifier loss in aggressive GI stromal tumours
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DOI：
10.1136/gutjnl-2015-309482
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发表时间：
2016-12-01
期刊：
影响因子：
24.5
通讯作者：
Tan, Patrick
中科院分区：
文献类型：
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作者：
Huang, Kie Kyon;McPherson, John R.;Tan, Patrick
胃肠道间质瘤（gist）在临床上是异质性的，在个体患者中表现出不同程度的疾病侵袭性。目的：我们试图确定与高风险GIST相关的遗传改变，探索其分子后果，并测试其作为预后标志物的效用。对18例gist患者（9例为高危/转移性患者，5例为低/中危患者）进行外显子组测序，分别对应11例原发肿瘤和7例转移性肿瘤。候选改变通过独立患者队列（n=120）的患病率筛查得到验证。在原代组织和细胞系中研究了SETD2突变的功能后果。分析了8份gist（4份SETD2突变，4份SETD2野生型）的转录组谱和22份gist（10份SETD2突变，12份SETD2野生型）的DNA甲基化谱。确定了分子、临床病理因素和无复发生存率之间的统计学关联。结果高危gist患者的体细胞突变数高于低危gist患者（25.2个突变/高危病例vs 6.8个突变/低危病例；两样本t检验p=3.1x10(-5)）。SETD2组蛋白修饰基因的体细胞改变发生在9例高风险/转移性病例中的3例中，但没有低/中危病例。流行筛查在80例高风险/转移性病例中发现了7例额外的SETD2突变，但没有低/中危病例（n=29）。合并后，SETD2在高危和低危gist中的突变频率分别为11.2%（10/89）和0%（0/34）。SETD2突变体gist显示H3K36me3表达降低，而SETD2沉默促进GIST-T1细胞的DNA损伤。在胃gist中，SETD2突变与HOXC簇基因的过表达和低甲基化异染色质的DNA甲基化特征相关。单变量分析显示，SETD2突变的胃gist或低甲基化异染色质的胃gist的无复发生存期显著缩短（log rank p=4.1x10(-5)）。结论：我们的数据表明SETD2是一种与疾病进展相关的新型GIST肿瘤抑制基因。评估SETD2遗传状态和SETD2相关的表观基因组表型可以指导风险分层，并为GIST临床侵袭性机制提供见解。
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=3.1x10(-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=4.1x10(-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.