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PLoS One. 2013 Aug 13;8(8):e72609. doi: 10.1371/journal.pone.0072609. eCollection 2013.

Clinical relevance of gain-of-function mutations of p53 in high-grade serous ovarian carcinoma.

Author information

1
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Abstract

PURPOSE:

Inactivation of TP53, which occurs predominantly by missense mutations in exons 4-9, is a major genetic alteration in a subset of human cancer. In spite of growing evidence that gain-of-function (GOF) mutations of p53 also have oncogenic activity, little is known about the clinical relevance of these mutations.

METHODS:

The clinicopathological features of high-grade serous ovarian carcinoma (HGS-OvCa) patients with GOF p53 mutations were evaluated according to a comprehensive somatic mutation profile comprised of whole exome sequencing, mRNA expression, and protein expression profiles obtained from the Cancer Genome Atlas (TCGA).

RESULTS:

Patients with a mutant p53 protein (mutp53) with a GOF mutation showed higher p53 mRNA and protein expression levels than patients with p53 mutation with no evidence of GOF (NE-GOF). GOF mutations were more likely to occur within mutational hotspots, and at CpG sites, and resulted in mutp53 with higher functional severity (FS) scores. Clinically, patients with GOF mutations showed a higher frequency of platinum resistance (22/58, 37.9%) than patients with NE-GOF mutations (12/56, 21.4%) (p=0.054). Furthermore, patients with GOF mutations were more likely to develop distant metastasis (36/55, 65.5%) than local recurrence (19/55, 34.5%), whereas patients with NE-GOF mutations showed a higher frequency of locoregional recurrence (26/47, 55.3%) than distant metastasis (21/47, 44.7%) (p=0.035). There were no differences in overall or progression-free survival between patients with GOF or NE-GOF mutp53.

CONCLUSION:

This study demonstrates that patient with GOF mutp53 is characterized by a greater likelihood of platinum treatment resistance and distant metastatic properties in HGS-OvCa.

PMID:
23967324
PMCID:
PMC3742716
DOI:
10.1371/journal.pone.0072609
[Indexed for MEDLINE]
Free PMC Article

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