TP53是一种主要的抑癌基因，在大约一半的人类癌症中发生突变。鉴于相应的p53蛋白具有多种调节作用，可以从基因表达模式中推断p53活性的丧失 - 这可能是由于转录后的改变所致。已知有几种类似于p53丧失的这种改变，但还可能存在其他的改变，但它们在人类肿瘤中的身份和普遍性尚未得到很好的表征。我们对约7,000个肿瘤和约1,000个细胞系的转录组进行了大规模的统计分析，估计约有12%和8%的肿瘤和癌症细胞系类似于TP53丧失：它们很可能缺乏p53通路的活性，同时不具有明显的TP53失活突变。虽然已知有一些这样的情况是由于已知的类似现象基因MDM2、MDM4和PPM1D的扩增引起的，但还有很多情况是未知的。癌症基因组评分联合CRISPR/RNAi遗传筛查数据的关联分析鉴定了另一个常见的TP53丧失类似基因USP28。USP28的缺失与乳腺、膀胱、肺、肝、胃等肿瘤中TP53功能受损相关，占2.9-7.6％，具有与MDM4扩增相当的效应大小。此外，在已知含有MDM2的拷贝数变异（CNA）片段中，我们鉴定了另一个共扩增的基因（CNOT2），它可能协同增强MDM2对TP53功能失活的影响。通过使用类似现象得分对癌细胞药物筛选进行分析表明，TP53的（不）活性通常调节抗癌药物效果和各种基因标记之间的关联，例如PIK3CA和PTEN突变，因此应被视为精准医学中的药物活性修饰因素。作为资源，我们提供了因TP53功能状态不同而不同的药物基因标记关联。在不具有明显的TP53遗传变异但出现p53活性丧失的人类肿瘤中，USP28基因的缺失很常见。©2023年该作者。

TP53 is a master tumor suppressor gene, mutated in approximately half of all human cancers. Given the many regulatory roles of the corresponding p53 protein, it is possible to infer loss of p53 activity - which may occur due to alterations in trans - from gene expression patterns. Several such alterations that phenocopy p53 loss are known, however additional ones may exist, but their identity and prevalence among human tumors are not well characterized.We perform a large-scale statistical analysis on transcriptomes of ~ 7,000 tumors and ~ 1,000 cell lines, estimating that 12% and 8% of tumors and cancer cell lines, respectively, phenocopy TP53 loss: they are likely deficient in the activity of the p53 pathway, while not bearing obvious TP53 inactivating mutations. While some of these cases are explained by amplifications in the known phenocopying genes MDM2, MDM4 and PPM1D, many are not. An association analysis of cancer genomic scores jointly with CRISPR/RNAi genetic screening data identified an additional common TP53-loss phenocopying gene, USP28. Deletions in USP28 are associated with a TP53 functional impairment in 2.9-7.6% of breast, bladder, lung, liver and stomach tumors, and have comparable effect size to MDM4 amplifications. Additionally, in the known copy number alteration (CNA) segment harboring MDM2, we identify an additional co-amplified gene (CNOT2) that may cooperatively boost the TP53 functional inactivation effect of MDM2. An analysis of cancer cell line drug screens using phenocopy scores suggests that TP53 (in)activity commonly modulates associations between anticancer drug effects and various genetic markers, such as PIK3CA and PTEN mutations, and should thus be considered as a drug activity modifying factor in precision medicine. As a resource, we provide the drug-genetic marker associations that differ depending on TP53 functional status.Human tumors that do not bear obvious TP53 genetic alterations but that phenocopy p53 activity loss are common, and the USP28 gene deletions are one likely cause.© 2023. The Author(s).