Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis

Abstract

TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma

“…The immune TME composition did not exhibit features that simultaneously distinguished double mutation from all other mutation configurations. Genome-wide expression analysis revealed a high number of differentially expressed genes between doublemutated tumours and TP53wt tumours, many of which were attributed to TP53 signalling and tumour cell proliferation, in line with earlier analyses of TP53-mutated tumours [18]. A smaller number of differentially expressed genes was detected between KRASmut/TP53mut and KRASwt/TP53mut tumours, resulting in an intersection of 64 genes that distinguished the double-mutant from all other KRAS/TP53 mutation configurations.…”

“…Tumours were classified according to activating or likely activating mutations (KRASmut tumours) and the remaining tumours (KRASwt tumours). TP53 mutations were classified into gain-of-function (GOF), loss-of-function (LOF), VUS, and neutral variants as described before [18]. Tumours were classified according to GOF or LOF mutations (TP53mut tumours), and the remaining tumours (TP53wt tumours).…”

Venetoclax Resistance in Acute Myeloid Leukemia

“…Consistently, resistant AML cells have often been associated with a decrease in the expression of pro-apoptotic BAX and NOXA [ 75 , 95 ]. Mechanistically, it is noticeable that TP53 transcriptionally regulates the expression of BAX and NOXA proteins [ 41 , 43 , 96 , 97 , 98 ], partially explaining the role of TP53 mutation in mediating VEN resistance. As a proof of concept, NOXA-deficient cells were shown to be resistant to the combination of VEN-AZA and PUMA in vitro [ 99 ], which epigenetically mediated deregulation, causing VEN resistance in lymphoid [ 100 ] and myeloid leukemias [ 101 ].…”