Prevalence, causes and impact of TP53-loss phenocopying events in human tumors
Abstract Background 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...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | BMC Biology |
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| Online Access: | https://doi.org/10.1186/s12915-023-01595-1 |
| _version_ | 1797836193529856000 |
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| author | Bruno Fito-Lopez Marina Salvadores Miguel-Martin Alvarez Fran Supek |
| author_facet | Bruno Fito-Lopez Marina Salvadores Miguel-Martin Alvarez Fran Supek |
| author_sort | Bruno Fito-Lopez |
| collection | DOAJ |
| description | Abstract Background 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. Results 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. Conclusions 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. |
| first_indexed | 2024-04-09T15:05:50Z |
| format | Article |
| id | doaj.art-0e83e71c9c774af0b871e2049e79e55c |
| institution | Directory Open Access Journal |
| issn | 1741-7007 |
| language | English |
| last_indexed | 2024-04-09T15:05:50Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Biology |
| spelling | doaj.art-0e83e71c9c774af0b871e2049e79e55c2023-04-30T11:28:17ZengBMCBMC Biology1741-70072023-04-0121112510.1186/s12915-023-01595-1Prevalence, causes and impact of TP53-loss phenocopying events in human tumorsBruno Fito-Lopez0Marina Salvadores1Miguel-Martin Alvarez2Fran Supek3Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology (BIST)Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute for Science and Technology (BIST)Abstract Background 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. Results 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. Conclusions 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.https://doi.org/10.1186/s12915-023-01595-1Tumor evolutionDriver genesp53 pathwayTranscriptomic signatureGene expressionCRISPR screens |
| spellingShingle | Bruno Fito-Lopez Marina Salvadores Miguel-Martin Alvarez Fran Supek Prevalence, causes and impact of TP53-loss phenocopying events in human tumors BMC Biology Tumor evolution Driver genes p53 pathway Transcriptomic signature Gene expression CRISPR screens |
| title | Prevalence, causes and impact of TP53-loss phenocopying events in human tumors |
| title_full | Prevalence, causes and impact of TP53-loss phenocopying events in human tumors |
| title_fullStr | Prevalence, causes and impact of TP53-loss phenocopying events in human tumors |
| title_full_unstemmed | Prevalence, causes and impact of TP53-loss phenocopying events in human tumors |
| title_short | Prevalence, causes and impact of TP53-loss phenocopying events in human tumors |
| title_sort | prevalence causes and impact of tp53 loss phenocopying events in human tumors |
| topic | Tumor evolution Driver genes p53 pathway Transcriptomic signature Gene expression CRISPR screens |
| url | https://doi.org/10.1186/s12915-023-01595-1 |
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