Abstract：
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.
摘要：
我们进行了一系列综合分析，包括肾细胞癌（RCC）的全转录组关联研究（TWAS）和全蛋白质组关联研究（PWAS），以提名和优先考虑实验室研究的分子靶标。根据对29,020名受影响个体和835,670名对照个体的全基因组关联研究（GWAS）以及在转录组参考模型中训练的预测模型，我们在四个肾脏转录组(GTEx肾皮质，肾小管,TCGA-KIRC[癌症基因组图谱肾肾透明细胞癌]，和TCGA-KIRP[TCGA肾乳头状细胞癌]）在四个转录组中的至少两个组中鉴定了38个基因关联（错误发现率<5％），并鉴定了12个独立于GWAS易感性区域的基因。结合来自GTEx的48个组织的TWAS关联的分析确定了在23个额外基因的肿瘤转录组中可复制的关联。两种主要组织学类型（透明细胞RCC和乳头状RCC）的分析显示了亚型特异性关联，尽管两种亚型至少有三种基因关联是共同的。PWAS鉴定出13种相关蛋白,所有映射到GWAS显著基因座。TWAS鉴定的基因富集了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。利用基因表达相关性，常见癌症(乳腺癌和前列腺癌)和RCC风险因素(例如，高血压和BMI）显示与RCC共有的遗传贡献。我们的工作确定了用于下游功能研究的RCC敏感性的潜在分子靶标。
