Large-scale human genetic data^1,2,3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)^4,5,6. VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization^6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. ⁸). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.

大规模人类基因数据^1,2,3表明癌症突变表现出很强的组织选择性，但这种选择性是如何产生的仍不清楚。在这里，使用实验模型、功能基因组学和对患者样本的分析，我们证明了谱系转录因子配对框 8 (PAX8) 是致癌信号传导所必需的，这两种基因改变会导致人类透明细胞肾细胞癌 (ccRCC)： 11q13.3 处的种系变异 rs7948643 和 von Hippel-Lindau 肿瘤抑制因子 ( VHL )的体细胞失活^4,5,6。在约 90% 的 ccRCC 中观察到VHL丢失可导致缺氧诱导因子 2α (HIF2A) 稳定^6,7. 我们显示 HIF2A 优先招募到 PAX8 结合的转录增强子，包括由 PAX8 和 HIF2A 控制的促肿瘤细胞周期蛋白 D1 ( CCND1 ) 增强子。rs7948643 处的 ccRCC 保护性等位基因 C 抑制 PAX8 在该增强子处的结合和CCND1表达的下游激活。在 8q21.3-q24.3 的 ccRCC 转移相关扩增子的MYC表达也需要共同选择支持正常肾上皮细胞增殖的 PAX8 依赖性生理程序（参考文献⁸）。这些结果表明，转录谱系因子对于致癌信号传导至关重要，并且它们介导与体细胞和遗传遗传变异相关的组织特异性癌症风险。