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肾系因子 PAX8 控制肾癌中的致癌信号。

The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.

机构信息

MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK.

Wellcome Sanger Institute, Cambridge, UK.

出版信息

Nature. 2022 Jun;606(7916):999-1006. doi: 10.1038/s41586-022-04809-8. Epub 2022 Jun 8.

DOI:10.1038/s41586-022-04809-8
PMID:35676472
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9242860/
Abstract

Large-scale human genetic data 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). VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization. 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. ). 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.

摘要

大规模人类遗传数据表明，癌症突变显示出强烈的组织选择性，但这种选择性是如何产生的尚不清楚。在这里，我们使用实验模型、功能基因组学和患者样本分析，证明了配对盒基因 8（PAX8）是两种常见遗传改变导致人类透明细胞肾细胞癌（ccRCC）所必需的致癌信号：胚系变异 rs7948643 在 11q13.3 和抑癌基因 von Hippel-Lindau（VHL）的体细胞失活。VHL 的缺失，约见于 90%的 ccRCC，可导致缺氧诱导因子 2α（HIF2A）的稳定。我们表明，HIF2A 优先被招募到 PAX8 结合的转录增强子，包括一个由 PAX8 和 HIF2A 控制的促肿瘤发生的细胞周期蛋白 D1（CCND1）增强子。rs7948643 的保护性等位基因 C 抑制了该增强子上 PAX8 的结合，以及下游 CCND1 表达的激活。PAX8 依赖性生理程序的共选择也需要 8q21.3-q24.3 处的 ccRCC 转移相关扩增子中的 MYC 表达，该程序支持正常肾上皮细胞的增殖（参考）。这些结果表明，转录谱系因子是致癌信号所必需的，它们介导与体细胞和遗传变异相关的组织特异性癌症风险。

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