GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors
GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors
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DOI：
10.1371/journal.pbio.3000434
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发表时间：
2019-11-01
期刊：
影响因子：
9.8
通讯作者：
Insel, Paul A.
中科院分区：
文献类型：
--
作者：
Sriram, Krishna;Moyung, Kevin;Insel, Paul A.
G蛋白偶联受体（gpcr）是美国食品和药物管理局（FDA）批准的药物中最广泛靶向的基因家族。为了评估GPCRs在癌症中的可能作用，我们分析了癌症基因组图谱（TCGA）数据中20类和45种实体肿瘤亚型的mRNA表达、突变和拷贝数变异（CNV），并通过将肿瘤与基因组织表达计划（GTEx）数据库中的正常组织进行比较，量化了GPCRs的差异表达（DE）。gpcr在实体瘤中表达升高的编码基因中被过度代表。该分析揭示了大多数肿瘤类型差异表达bbbb50 gpcr，包括许多已批准药物的靶标，迄今为止在很大程度上未被识别为癌症的靶标。GPCR mRNA特征表征特定的肿瘤类型，并与癌症相关途径的表达相关。肿瘤GPCR mRNA特征与生存预后相关，并与许多癌症相关基因和途径的表达相关。GPCR在肿瘤中的表达在很大程度上与分期、分级、转移和/或驱动突变无关。GPCR在肿瘤细胞系中的表达与GPCR在肿瘤中的表达基本平行。某些gpcr经常发生突变，似乎是热点，作为累积基因组损伤的风向标。gpcr的CNV是常见的，但通常与mRNA表达无关。我们的研究结果表明，gpcr在癌症中的作用以前被低估了，可能是作为功能性癌基因、生物标志物、表面抗原和药理学靶点。
G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs. To assess possible roles for GPCRs in cancer, we analyzed The Cancer Genome Atlas (TCGA) data for mRNA expression, mutations, and copy number variation (CNV) in 20 categories and 45 subtypes of solid tumors and quantified differential expression (DE) of GPCRs by comparing tumors against normal tissue from the Gene Tissue Expression Project (GTEx) database. GPCRs are overrepresented among coding genes with elevated expression in solid tumors. This analysis reveals that most tumor types differentially express >50 GPCRs, including many targets for approved drugs, hitherto largely unrecognized as targets of interest in cancer. GPCR mRNA signatures characterize specific tumor types and correlate with expression of cancer-related pathways. Tumor GPCR mRNA signatures have prognostic relevance for survival and correlate with expression of numerous cancer-related genes and pathways. GPCR expression in tumors is largely independent of staging, grading, metastasis, and/or driver mutations. GPCRs expressed in cancer cell lines largely parallel GPCR expression in tumors. Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage. CNV of GPCRs is common but does not generally correlate with mRNA expression. Our results suggest a previously underappreciated role for GPCRs in cancer, perhaps as functional oncogenes, biomarkers, surface antigens, and pharmacological targets.