Clinical relevance of TP53 hotspot mutations in high-grade serous ovarian cancers
Abstract
Background
Mutation ofTP53is the most frequent genetic alteration in high-grade serous ovarian cancer (HGSOC). The impact of hotspot mutations ofTP53and protein levels on patient outcomes in HGSOC has not been fully elucidated.
Methods
The study population (n = 791) comprised of HGSOC samples withTP53mutation from TCGA and other publicly available data. Univariate and multivariate cox proportional hazards regression analyses were used to select variables that were correlated with patient survival.
Results
We assessed the effects ofTP53mutations based on type and individual hotspot mutations on patient outcomes in HGSOC. Only hotspot mutations were associated with outcomes. Three hotspot mutations: G266, Y163C, and R282, in aggregate were associated with a worsened overall and recurrence-free survival compared with other hotspot mutations (p < 0.0001 andp = 0.001), other non-hotspot missense mutations (p < 0.0001 andp = 0.008), truncated mutations (p < 0.0001 andp = 0.001), and all other mutations (p < 0.0001 andp = 0.001). Specific hotspot mutations were associated with different protein expression patterns consistent with different functions.
Conclusions
This study provides evidence that individualTP53hotspot mutations have different impact on HGSOC patient outcomes and potentially TP53 function. Thus the status of particularTP53aberrations could influence response to therapy and selection of therapeutic agents.