title: H2AX phosphorylation level in peripheral blood mononuclear cells as an event-free survival predictor for bladder cancer.
abstract: Bladder cancer (BC) has a typical aetiology characterized by a multistep carcinogenesis due to environmental exposures, genetic susceptibility, and their interaction. Several lines of evidence suggest that DNA repair plays a role in the development and progression of BC. In particular, the study of individual susceptibility to DNA double strand breaks (DSBs) may provide valuable information on BC risk, and help to identify those patients at high-risk of either recurrence or progression of the disease, possibly personalizing both surveillance and treatment. Among the different DSB markers, the most well characterized is phosphorylation of the histone H2AX (γ-H2AX). We assessed any potential role of γ-H2AX as a molecular biomarker in a case-control study (146 cases and 146 controls) to identify individuals with increased BC risk and at high-risk of disease recurrence or progression. We investigated γ-H2AX levels in peripheral blood mononuclear cells before and after their exposure to ionizing radiation (IR). We did not find any significant difference among cases and controls. However, we observed a significant association between γ-H2AX basal levels and risk of disease recurrence or progression. In particular, both BC patients as a whole and the subgroup of non-muscle invasive BC (NMIBC) with high basal H2AX phosphorylation levels had a decreased risk of recurrence or progression (for all BC HR 0.70, 95%CI 0.52-0.94, P = 0.02; for NMIBC HR 0.68, 95%CI 0.50-0.92, P = 0.01), suggesting a protective effect of basal DSB signaling. Our data suggest that γ-H2AX can be considered as a potential molecular biomarker to identify patients with a higher risk of BC recurrence. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy. valentina.turinetto@unito.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Turinetto
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy. barbara.pardini@hugef.org.|Department of Medical Sciences, University of Turin, Turin, Italy. barbara.pardini@hugef.org.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Allione
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fiorito
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Viberti
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Oncology, Radiation Oncology Unit, S. Luigi Hospital, University of Turin, Orbassano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Anglesio
authors.affiliation: Department of Oncology, Radiation Oncology Unit, S. Luigi Hospital, University of Turin, Orbassano, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Ruo Redda
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casetta
authors.affiliation: Department of Urology, Clinica Cellini, Turin, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Cucchiarale
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Destefanis
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Oderda
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gontero
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Rolle
authors.affiliation: Department of Urology, Città della Salute e della Scienza, Turin, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Frea
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Center for Cancer Prevention (CPO-Piemonte), Turin, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Giachino
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D018450:Disease Progression; D018572:Disease-Free Survival; D006657:Histones / Q000097:blood*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D016019:Survival Analysis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D006657:Histones
keywords: H2AX phosphorylation assay; bladder cancer; event-free survival; overall survival; peripheral blood mononuclear cells