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Survival in males with glioma and gastric adenocarcinoma correlates with mutant p53 residual transcriptional activity.
Fischer, Nicholas W; Prodeus, Aaron; Gariépy, Jean.
Afiliación
  • Fischer NW; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • Prodeus A; Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.
  • Gariépy J; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
JCI Insight ; 3(15)2018 08 09.
Article en En | MEDLINE | ID: mdl-30089713
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).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Neoplasias Encefálicas / Adenocarcinoma / Proteína p53 Supresora de Tumor / Glioma Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: America do norte Idioma: En Revista: JCI Insight Año: 2018 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Gástricas / Neoplasias Encefálicas / Adenocarcinoma / Proteína p53 Supresora de Tumor / Glioma Tipo de estudio: Observational_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Female / Humans / Male / Middle aged País/Región como asunto: America do norte Idioma: En Revista: JCI Insight Año: 2018 Tipo del documento: Article País de afiliación: Canadá
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