expression ranged from 399 genes in

其表达范围从OV中的399个基因到睾丸生殖细胞肿瘤中的4,795个基因（TGCT；图3b）。miRNA表达的变化范围从皮肤皮肤黑色素瘤（SKCM）中的2到THYM中的213。胃腺癌（STAD）在蛋白质水平上显示出最大的变化，而THYM在DNA甲基化中显示出最大的变化，而BRCA显示出最多的SCNA。跨多层缺氧相关特征的总数也有所不同。例如，STAD在六个分子层具有许多低氧相关特征，包括4,169个mRNA，186个miRNA，91个蛋白质，294个甲基化探针，1个基因突变和10个SCNA，而多形胶质母细胞瘤（GBM）在629个mRNA和5个中具有低氧相关特征。蛋白质。此外，先前的研究表明低氧状态对代谢组学的影响。基于来自23个TCGA BRCA样品的399种代谢物，我们观察到86种代谢物与缺氧评分呈正相关（r> 0.3，P <0.05；补充图4a）。我们进一步确定了7种低氧评分高样本中45种代谢产物上调，而6种低氧评分低样本中该代谢产物被上调（双面学生t检验，P <0.05；补充图4b）。这些结果概述了肿瘤谱系中与低氧状态相关的分子差异.4243s 补充图4b）。这些结果概述了肿瘤谱系中与低氧状态相关的分子差异.4243s 补充图4b）。这些结果概述了肿瘤谱系中与低氧状态相关的分子差异.4243s<br><br>为了评估缺氧相关特征对药物反应的潜在影响，我们针对至少9种癌症类型中的1,060个具有至少一种缺氧相关分子标记的基因进行了研究。我们从1,074个癌细胞系的癌症药物敏感性基因组学（GDSC）中，计算了这些基因的表达与252种抗癌药物的药物敏感性之间的Spearman秩相关性。这些抗癌药物靶向多种生物学过程，包括染色质标记，细胞周期，代谢，EGFR信号传导和受体酪氨酸激酶（RTK）信号传导途径。我们鉴定了143个与缺氧相关的基因，这些基因与至少三种抗癌药物的敏感性显着相关（| r |> 0.3，FDR <0.05；图3c，补充图5和补充数据2）。例如，在低氧评分高的9种癌症样本中，转录共激活因子YAP1的蛋白水平上调；其mRNA表达与对49种抗癌药物的耐药性有关（例如，navitoclax，r = 0.52，FDR <1.0×10），并与对5种抗癌药物的药物敏感性有关（例如，多西他赛，r = −0.42，FDR = 1.7×10）。RTK信号通路的失调是多种癌症类型的既定特征，可以刺激RTK信号44ss-55s-35

expression ranged from 399 genes in OV to 4,795 genes in testicular germ cell tumours (TGCTs; Fig. 3b). Alterations of miRNA expression ranged from 2 in skin cutaneous melanoma (SKCM) to 213 in THYM. Stomach adenocarcinoma (STAD) showed the largest number of alterations at the protein level, while THYM showed the largest number of alterations in DNA methylation and BRCA showed the largest number of SCNAs. The total number of hypoxia-associated features across multiple layers also varied. For example, STAD had many hypoxiaassociated features in six molecular layers, including 4,169 mRNAs, 186 miRNAs, 91 proteins, 294 methylation probes, 1 gene mutation and 10 SCNAs, while glioblastoma multiforme (GBM) had hypoxia-associated features in 629 mRNAs and 5 proteins. Furthermore, previous studies demonstrated the effects of hypoxia status on metabolomics. Based on 399 metabolites from 23 TCGA BRCA samples, we observed that 86 metabolites positively correlated with hypoxia score (r > 0.3, P < 0.05; Supplementary Fig. 4a). We further identified 45 metabolites that were upregulated in 7 hypoxia score-high samples compared to 6 hypoxia score-low samples (two-sided Student's t-test, P < 0.05; Supplementary Fig. 4b). These results provide an overview of the molecular differences associated with hypoxia status across tumour lineages.4243s<br><br>To assess the potential effects of hypoxia-associated features on drug response, we focused on 1,060 genes with at least 1 type of hypoxia-associated molecular signature in at least 9 cancer types. We calculated Spearman's rank correlations between the expression of these genes and drug sensitivity for 252 anticancer drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) across 1,074 cancer cell lines. These anticancer drugs target multiple biological processes, including the chromatin signature, cell cycle, metabolism, EGFR signalling and receptor tyrosine kinase (RTK) signalling pathways. We identified 143 hypoxia-associated genes that significantly correlated with the sensitivity of at least three anticancer drugs (|r| > 0.3, FDR < 0.05; Fig. 3c, Supplementary Fig. 5 and Supplementary Data 2). For example, the protein level of transcriptional coactivator YAP1 is upregulated in hypoxia score-high samples in nine cancer types; its mRNA expression is linked to drug resistance to 49 anticancer drugs (for example, navitoclax, r = 0.52, FDR < 1.0 × 10) and linked to drug sensitivity to five anticancer drugs in (for example, docetaxel, r = −0.42, FDR = 1.7 × 10). Dysregulation of the RTK signalling pathway is an established feature in multiple cancer types and RTK signalling can be stimulated44ss−55s−35

在OV中的表达范围从399个基因到睾丸生殖细胞肿瘤中的4795个基因（TGCT；图3b）。miRNA表达的改变范围从皮肤黑色素瘤（SKCM）的2到胸腺的213。胃腺癌（STAD）表现出最大数量的蛋白质水平的改变，而胸腺表现出最大数量的DNA甲基化改变，BRCA表现出最大数量的SCNAs。缺氧相关的多层面特征的总数也各不相同。例如，STAD在6个分子层中具有许多低氧相关特征，包括4169个mRNAs、186个miRNAs、91个蛋白质、294个甲基化探针、1个基因突变和10个SCNAs；多形性胶质母细胞瘤（glioblastoma multiforme，GBM）在629个mRNAs和5个蛋白质层中具有低氧相关特征。此外，以往的研究表明缺氧状态对代谢组学的影响。基于23个TCGA BRCA样本的399种代谢物，我们观察到86种代谢物与缺氧评分呈正相关（r>0.3，P