Clinical Relevance of Gain-Of-Function Mutations of p53 in High-Grade Serous Ovarian Carcinoma

Hyo Jeong Kang,Insuk Sohn,Sung-Min Chun,Chang Ohk Sung,Kyu-Rae Kim,Eric Asselin

doi:10.1371/journal.pone.0072609

Hyo Jeong Kang, Insuk Sohn + Show 4 more

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https://doi.org/10.1371/journal.pone.0072609

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Abstract

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

Highlights

Loss of p53 function is a common feature in human cancers [1] and mutation is a major cause of loss of p53 function in a subset of tumor
We evaluated the clinicopathological features of tumors with hotspot or GOF mutations of TP53 using a comprehensive somatic mutation profile comprised of whole exome sequencing, mRNA expression profiles, and protein expression profiles obtained from The Cancer Genome Atlas (TCGA)
Hotspot mutations were located in the area of TP53 cDNA with the highest GC content (Figure 1A), and hotspot mutations were significantly associated with CpG sites (p

Summary

Introduction

Loss of p53 function is a common feature in human cancers [1] and mutation is a major cause of loss of p53 function in a subset of tumor. While other tumor suppressors, such as RB, APC, or BRCA1, are commonly inactivated by frame-shift or nonsense mutations, missense mutation is predominant type in TP53 mutation in human tumors These mutations occur primarily in exons 4–9, which encode the DNA-binding domain of the protein [2,3]. Many mutant forms of p53 can bind and inactivate p53-related proteins such as p63 and p73 [4] This additional oncogenic activity of mutp has been described as gain-of-function (GOF), which was demonstrated to drive tumor cells toward migration, invasion, and metastasis in mouse models [5,6,7,8,9,10]. Little is known about the clinical relevance of GOF mutp, and there is so far no concrete evidence that GOF mutations in p53 contribute to clinical behavior in human cancers

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