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. Further investigation revealed that, like mutant p53, the HIF1/ARNT hypoxia pathway was not required for the primary tumor functions of advanced mutant p53 gastric cancer. These findings indicate that recurrent p53 mutations in gastroesophageal adenocarcinoma are unlikely to serve as effective therapeutic targets in advanced cancer. However, in elucidating the contribution of missense mutant p53 and hypoxia signaling, the results suggest hypotheses regarding how these recurrent genomic events may contribute to gastric and esophageal adenocarcinoma formation.
Nilay Sethi, Osamu Kikuchi, James McFarland, Yanxi Zhang, Max Chung, Nicholas Kafker, Mirazul Islam, Benjamin Lampson, Abhishek Chakraborty, William G. Kaelin Jr., Adam J. Bass
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