Von Hippel-Lindau（VHL）肿瘤抑制基因的双等位基因失活在绝大多数透明细胞肾细胞癌（ccRCC）病例中发生，破坏细胞氧感知机制，产生持续的假性低氧状态，即在存在足够 氧气水平的情况下持续产生低氧反应。然而，单独丢失VHL通常是不足以驱动致癌的。基因组研究的结果显示，VHL与三个编码涉及染色质修饰和重塑蛋白的基因之一（或多个）的共同缺失，多溴-1基因（PBRM1）、BRCA1相关蛋白质1（BAP1）和含SET区域的蛋白2（SETD2），是常见且重要的肿瘤发生共同驱动程序。这些基因都位于染色体3p上的VHL附近，往往在细胞遗传学重排后发生变化，导致3p缺失并引发ccRCC的建立。这三种蛋白在调节关键的癌症相关通路方面起着多种作用，包括保护基因组稳定性，在生理条件下拮抗多组蛋白（PcG）复合物，维护可渗透的转录景观以及调节介导免疫检查点抑制剂疗法反应的基因。对这些机制的更好理解将带来新的见解，有关ccRCC生长和治疗反应的细胞驱动因子，并最终支持新型译码治疗的开发。 ©2022 Springer Nature Limited.

Biallelic inactivation of the tumour suppressor gene Von Hippel-Lindau (VHL) occurs in the vast majority of clear cell renal cell carcinoma (ccRCC) instances, disrupting cellular oxygen-sensing mechanisms to yield a state of persistent pseudo-hypoxia, defined as a continued hypoxic response despite the presence of adequate oxygen levels. However, loss of VHL alone is often insufficient to drive oncogenesis. Results from genomic studies have shown that co-deletions of VHL with one (or more) of three genes encoding proteins involved in chromatin modification and remodelling, polybromo-1 gene (PBRM1), BRCA1-associated protein 1 (BAP1) and SET domain-containing 2 (SETD2), are common and important co-drivers of tumorigenesis. These genes are all located near VHL on chromosome 3p and are often altered following cytogenetic rearrangements that lead to 3p loss and precede the establishment of ccRCC. These three proteins have multiple roles in the regulation of crucial cancer-related pathways, including protection of genomic stability, antagonism of polycomb group (PcG) complexes to maintain a permissive transcriptional landscape in physiological conditions, and regulation of genes that mediate responses to immune checkpoint inhibitor therapy. An improved understanding of these mechanisms will bring new insights regarding cellular drivers of ccRCC growth and therapy response and, ultimately, will support the development of novel translational therapeutics.© 2022. Springer Nature Limited.