Residual mutant p53 activity linked to cancer survival in males
Spontaneous mutations in the gene encoding the tumor suppressor p53 (TP53) are frequently identified in human cancers and most of these mutations are the result of missense substitutions, which can result in complete loss of p53 function or retention of some activity. In this episode, Jean Gariépy and Nicholas Fischer discuss their work, which reveals that the level of residual transcriptional activity of mutant p53 associates with improved survival in males with glioma and gastric adenocarcinoma. This association was sex-specific, as similar links were not observed in females with p53-mutant cancers. Moreover, evaluation of patients with Li-Fraumeni syndrome (LFS), which results from germline mutations in TP53 revealed a link between residual p53 activity and prolong lifetime cancer survival. Together, these results support p53 transcriptional activity as a prognostic factor for men with glioma and gastric adenocarcinoma.
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Citation Information: JCI Insight. 2018;3(15):e121364. https://doi.org/10.1172/jci.insight.121364.
Abstract
BACKGROUND. There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS. This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant–specific residual transcriptional activity scores. RESULTS. Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4–3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7–5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7–3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8–2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). CONCLUSION. The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. FUNDING. Canadian Institutes of Health Research (no. 148556).
Authors
Nicholas W. Fischer, Aaron Prodeus, Jean Gariépy
