Turinetto Valentina, Pardini Barbara, Allione Alessandra, Fiorito Giovanni, Viberti Clara, Guarrera Simonetta, Russo Alessia, Anglesio Silvia, Ruo Redda Maria Grazia, Casetta Giovanni, Cucchiarale Giuseppina, Destefanis Paolo, Oderda Marco, Gontero Paolo, Rolle Luigi, Frea Bruno, Vineis Paolo, Sacerdote Carlotta, Giachino Claudia, Matullo Giuseppe
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, Italy.
Human Genetics Foundation (HuGeF), Turin, Italy.
Mol Carcinog. 2016 Nov;55(11):1833-1842. doi: 10.1002/mc.22431. Epub 2015 Nov 19.
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.
膀胱癌（BC）具有典型的病因，其特征是由于环境暴露、遗传易感性及其相互作用导致的多步骤致癌过程。多条证据表明，DNA修复在膀胱癌的发生和发展中起作用。特别是，对个体对DNA双链断裂（DSB）易感性的研究可能为膀胱癌风险提供有价值的信息，并有助于识别那些疾病复发或进展风险高的患者，从而可能实现监测和治疗的个性化。在不同的DSB标志物中，最具特征的是组蛋白H2AX（γ-H2AX）的磷酸化。我们在一项病例对照研究（146例病例和146例对照）中评估了γ-H2AX作为分子生物标志物的任何潜在作用，以识别膀胱癌风险增加以及疾病复发或进展风险高的个体。我们研究了外周血单个核细胞在暴露于电离辐射（IR）之前和之后的γ-H2AX水平。我们在病例和对照之间未发现任何显著差异。然而，我们观察到γ-H2AX基础水平与疾病复发或进展风险之间存在显著关联。特别是，总体膀胱癌患者以及基础H2AX磷酸化水平高的非肌层浸润性膀胱癌（NMIBC）亚组的复发或进展风险均降低（总体膀胱癌患者的风险比[HR]为0.70，95%置信区间[CI]为0.52-0.94，P = 0.02；NMIBC患者的HR为0.68，95%CI为0.50-0.92，P = 0.01），这表明基础DSB信号具有保护作用。我们的数据表明，γ-H2AX可被视为一种潜在的分子生物标志物，用于识别膀胱癌复发风险较高的患者。© 2015威利期刊公司
