Gastrointestinal stromal tumors: a case-only analysis of single nucleotide polymorphisms and somatic mutations.
Gastrointestinal stromal tumors: a case-only analysis of single nucleotide polymorphisms and somatic mutations.
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DOI：
10.1186/2045-3329-3-12
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发表时间：
2013-10-26
影响因子：
--
通讯作者：
Engel LS
中科院分区：
文献类型：
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作者：
O'Brien KM;Orlow I;Antonescu CR;Ballman K;McCall L;Dematteo R;Engel LS
胃肠道间质瘤是一种罕见的软组织肉瘤，通常由KIT或PDGFRA癌基因获得性功能获得性突变的间充质细胞发展而来。这些体细胞突变已经得到了很好的表征，但对遗传性遗传风险因素知之甚少。鉴于某些易感基因座和致癌物与其他癌症的特征性突变相关的证据，我们假设这些标志性KIT或PDGFRA突变可能对理解胃肠道间质瘤病因具有相似的基础性。因此，我们研究了522个单核苷酸多态性与7种KIT或PDGFRA肿瘤突变类型之间的关联。候选途径包括二恶英反应，毒素代谢，基质金属蛋白酶的生产，免疫和炎症反应。我们估计了来自甲磺酸伊马替尼辅助治疗临床试验的279名个体中每个候选SNP与肿瘤突变类型之间关联的比值比和95%置信区间。我们使用序列内核关联测试来寻找路径级关联。经多重比较校正后，ITGAE上的rs 1716变异与KIT外显子11非密码子557-8缺失显著相关（比值比= 2.86，95%置信区间：1.71-4.78）。其他值得注意的相关性包括rs3024498（IL 10）和rs 1050783（F13 A1）与PDGFRA突变，rs 2071888（TAPBP）与野生型肿瘤和几种基质金属蛋白酶SNP与KIT外显子11密码子557-558缺失。几种途径与PDGFRA的体细胞突变密切相关，包括防御反应（p = 0.005）和免疫反应的负调节（p = 0.01）。这项探索性分析为胃肠道间质瘤病因学提供了新的见解，并为未来研究该疾病的遗传和环境风险因素提供了起点。
Gastrointestinal stromal tumors are rare soft tissue sarcomas that typically develop from mesenchymal cells with acquired gain-in-function mutations in KIT or PDGFRA oncogenes. These somatic mutations have been well-characterized, but little is known about inherited genetic risk factors. Given evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations in other cancers, we hypothesized that these signature KIT or PDGFRA mutations may be similarly fundamental to understanding gastrointestinal stromal tumor etiology. Therefore, we examined associations between 522 single nucleotide polymorphisms and seven KIT or PDGFRA tumor mutations types. Candidate pathways included dioxin response, toxin metabolism, matrix metalloproteinase production, and immune and inflammatory response. We estimated odds ratios and 95% confidence intervals for associations between each candidate SNP and tumor mutation type in 279 individuals from a clinical trial of adjuvant imatinib mesylate. We used sequence kernel association tests to look for pathway-level associations. One variant, rs1716 on ITGAE, was significantly associated with KIT exon 11 non-codon 557–8 deletions (odds ratio = 2.86, 95% confidence interval: 1.71-4.78) after adjustment for multiple comparisons. Other noteworthy associations included rs3024498 (IL10) and rs1050783 (F13A1) with PDGFRA mutations, rs2071888 (TAPBP) with wild type tumors and several matrix metalloproteinase SNPs with KIT exon 11 codon 557–558 deletions. Several pathways were strongly associated with somatic mutations in PDGFRA, including defense response (p = 0.005) and negative regulation of immune response (p = 0.01). This exploratory analysis offers novel insights into gastrointestinal stromal tumor etiology and provides a starting point for future studies of genetic and environmental risk factors for the disease.