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Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

ABSTRACT: Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis revealed that hypoxia signaling was induced by mutant p53 in 2 gastric cancer cell lines. Using real-time in vivo imaging, we confirmed that hypoxia reporter activity was elevated during the initiation of mutant p53 gastric cancer xenografts. Unlike HIF co-factor ARNT, HIF1? was required for primary tumor growth in mutant p53 gastric cancer. These findings elucidate the contribution of missense p53 mutations in gastroesophageal malignancy and indicate that hypoxia signaling rather than mutant p53 itself may serve as a therapeutic vulnerability in these deadly set of cancers.

SUBMITTER: Sethi N

PROVIDER: S-EPMC6693823 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

Sethi Nilay N Kikuchi Osamu O McFarland James J Zhang Yanxi Y Chung Max M Kafker Nicholas N Islam Mirazul M Lampson Benjamin B Chakraborty Abhishek A Kaelin William G WG Bass Adam J AJ

JCI insight 20190808 15

Despite the propensity for gastric and esophageal adenocarcinomas to select for recurrent missense mutations in TP53, the precise functional consequence of these mutations remains unclear. Here we report that endogenous mRNA and protein levels of mutant p53 were elevated in cell lines and patients with gastric and esophageal cancer. Functional studies showed that mutant p53 was sufficient, but not necessary, for enhancing primary tumor growth in vivo. Unbiased genome-wide transcriptome analysis ...[more]

PMID: 31391338

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Project description: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).

Dataset Information

Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

Publications

Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma.

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