Increased Oxidative Damage in Carriers of the Germline TP53 p.R337H Mutation

Gabriel S Macedo,Vanusa Manfredini,Leonardo Lisbôa Da Motta,Fábio Klamt,Camila S.Vanzin,Pierre Hainaut,Cristina B O Netto,Patricia Ashton-Prolla,Juliana Giacomazzi,Carmen Regla Vargas

doi:10.1371/journal.pone.0047010

Abstract

Germline mutations in TP53 are the underlying defect of Li-Fraumeni Syndrome (LFS) and Li-Fraumeni-like (LFL) Syndrome, autosomal dominant disorders characterized by predisposition to multiple early onset cancers. In Brazil, a variant form of LFS/LFL is commonly detected because of the high prevalence of a founder mutation at codon 337 in TP53 (p.R337H). The p53 protein exerts multiple roles in the regulation of oxidative metabolism and cellular anti-oxidant defense systems. Herein, we analyzed the redox parameters in blood samples from p.R337H mutation carriers (C, n = 17) and non-carriers (NC, n = 17). We identified a significant increase in erythrocyte GPx activity and in plasma carbonyl content,an indicator of protein oxidative damage, in mutation carriers compared to non-carriers (P = 0.048 and P = 0.035, respectively). Mutation carriers also showed a four-fold increase in plasma malondialdehyde levels, indicating increased lipid peroxidation (NC = 40.20±0.71, C = 160.5±0.88, P<0.0001). Finally, carriers showed increased total antioxidant status but a decrease in plasma ascorbic acid content. The observed imbalance could be associated with deregulated cell bioenergetics and/or with increased inflammatory stress, two effects that may result from loss of wild-type p53 function. These findings provide the first evidence that oxidative damage occurs in carriers of a germline TP53 mutation, and these may have important implications regarding our understanding of the mechanisms responsible for germline TP53 p.R337H mutation-associated carcinogenesis.

Highlights

Li-Fraumeni Syndrome (LFS) and its variant, Li-Fraumenilike Syndrome (LFL), are autosomal dominant disorders characterized by increased predisposition to multiple early-onset cancers [1]
Number of individuals considered after exclusion of measurements 62 S.D from the mean are given in parenthesis. doi:10.1371/journal.pone.0047010.t002
A number of studies have shown that p53 operates as a regulator of cell oxidative metabolism and energy production [31,32,33]

Summary

Introduction

Li-Fraumeni Syndrome (LFS) and its variant, Li-Fraumenilike Syndrome (LFL), are autosomal dominant disorders characterized by increased predisposition to multiple early-onset cancers [1]. The core tumors of the syndrome are soft tissue and bone sarcomas, brain tumors, breast cancer, and adrenocortical carcinoma (ACC). Other malignancies such as leukemia, melanomas, and lung, gastric, pancreatic, prostate, and colorectal cancers have been described in several families [2,3,4,5]. Germline mutations in the TP53 gene are the only known genetic defect underlying LFS/LFL. About 56% of the families that meet the strict ‘‘classic’’ criteria for LFS have germline TP53 mutations. In LFL families, mutations are detected in about 36%, 16%, and 14% of probands that meet criteria of Chompret, Birch, and Eeles, respectively [6]

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Results

Conclusion