We performed a series of integrative analyses including transcriptome-wide association studies (TWASs) and proteome-wide association studies (PWASs) of renal cell carcinoma (RCC) to nominate and prioritize molecular targets for laboratory investigation. On the basis of a genome-wide association study (GWAS) of 29,020 affected individuals and 835,670 control individuals and prediction models trained in transcriptomic reference models, our TWAS across four kidney transcriptomes (GTEx kidney cortex, kidney tubules, TCGA-KIRC [The Cancer Genome Atlas kidney renal clear-cell carcinoma], and TCGA-KIRP [TCGA kidney renal papillary cell carcinoma]) identified 38 gene associations (false-discovery rate <5%) in at least two of four transcriptomic panels and identified 12 genes that were independent of GWAS susceptibility regions. Analyses combining TWAS associations across 48 tissues from GTEx identified associations that were replicable in tumor transcriptomes for 23 additional genes. Analyses by the two major histologic types (clear-cell RCC and papillary RCC) revealed subtype-specific associations, although at least three gene associations were common to both subtypes. PWAS identified 13 associated proteins, all mapping to GWAS-significant loci. TWAS-identified genes were enriched for active enhancer or promoter regions in RCC tumors and hypoxia-inducible factor binding sites in relevant cell lines. Using gene expression correlation, common cancers (breast and prostate) and RCC risk factors (e.g., hypertension and BMI) display genetic contributions shared with RCC. Our work identifies potential molecular targets for RCC susceptibility for downstream functional investigation.

中文翻译：

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转录组和蛋白质组范围的关联研究确定了与肾细胞癌相关的基因


我们进行了一系列综合分析，包括肾细胞癌 （RCC） 的转录组范围关联研究 （TWAS） 和蛋白质组范围关联研究 （PWAS），以提名和优先考虑实验室研究的分子靶点。根据对 29,020 名受影响个体和 835,670 名对照个体进行的全基因组关联研究 （GWAS） 和在转录组参考模型中训练的预测模型，我们跨四个肾脏转录组（GTEx 肾皮层、肾小管、TCGA-KIRC [癌症基因组图谱肾透明细胞癌] 和 TCGA-KIRP [TCGA 肾状细胞癌]）的 TWAS 在四种转录组学中的至少两种中确定了 38 个基因关联（错误发现率 <5%）面板并鉴定了 12 个独立于 GWAS 易感区域的基因。结合 GTEx 中 48 个组织的 TWAS 关联的分析确定了在肿瘤转录组中可复制的 23 个其他基因的关联。对两种主要组织学类型 （透明细胞 RCC 和状 RCC） 的分析揭示了亚型特异性关联，尽管两种亚型至少有三个基因关联是共同的。PWAS 鉴定了 13 种相关蛋白，均定位于 GWAS 显著位点。TWAS 鉴定的基因富集于 RCC 肿瘤中的活性增强子或启动子区域以及相关细胞系中的缺氧诱导因子结合位点。使用基因表达相关性，常见癌症 （乳腺癌和前列腺癌） 和 RCC 危险因素 （例如高血压和 BMI） 显示出与 RCC 相同的遗传贡献。我们的工作确定了 RCC 易感性的潜在分子靶标，用于下游功能研究。