Walker Simon R, Abdelsalam Ramy, Ghosh Sunita, Livingstone Julie, Palanisamy Nallasivam, Boutros Paul C, Yip Steven M, Lees-Miller Susan P, Bismar Tarek A
Department of Pathology and Laboratory Medicine, University of Calgary Cumming School of Medicine and Alberta Precision Laboratories, Calgary, AB, Canada.
Department of Medical Oncology, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services-Cancer Control, Edmonton, AB, Canada.
Eur Urol Open Sci. 2021 Jun 12;29:93-101. doi: 10.1016/j.euros.2021.05.004. eCollection 2021 Jul.
Ataxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa).
To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status.
This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP).
TURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM).
Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM ( = 0.015 and = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34-3.27, = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups.
Decreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor-targeted therapies, as well as platinum-based chemotherapies.
Lower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.
共济失调毛细血管扩张症突变（ATM）丝氨酸/苏氨酸蛋白激酶是一种已知的肿瘤抑制因子，参与DNA损伤修复。它具有预后和预测治疗意义，与侵袭性前列腺癌（PCa）相关。
探讨ATM蛋白表达在PCa患者中的预后价值，并评估ATM、ERG和PTEN状态的综合价值。
设计、设置和参与者：本研究包括303例经尿道前列腺切除术（TURP）的偶发性、局部晚期和去势抵抗性PCa患者。
对303例PCa患者的TURP样本进行免疫组织化学评估（ATM、ERG和PTEN的免疫组化）。个体和联合标志物状态与国际泌尿病理学会Gleason分级组、总生存期（OS）和PCa特异性死亡率（PCSM）相关。
164/303（54.1%）例患者出现ATM表达降低（阴性/弱阳性），且与较短的OS和较高的PCSM相关（分别为P = 0.015和P = 0.001）。ATM阴性/弱阳性表达与PCSM显著相关，风险比为2.09（95%置信区间1.34 - 3.27，P = 0.001）。联合ATM/PTEN表达评估显示，预测OS和PCSM的预后能力有所提高，且独立于Gleason分级组。
ATM蛋白表达降低与晚期PCa患者的不良预后相关。ATM/PTEN低表达联合阴性的患者OS降低和PCSM增加的风险最高。通过免疫组化评估PCa患者的ATM/PTEN联合状态可能有助于相对于OS和PCSM进行风险分层。此外，由于ATM在DNA损伤反应途径中起不可或缺的作用，未来的研究将增进我们对如何通过聚ADP核糖聚合酶抑制剂（PARPi）、PARPi与雄激素受体靶向治疗的联合应用以及铂类化疗进一步改善ATM和PTEN表达改变患者预后的理解。
较低的ATM强度与前列腺癌患者癌症特异性死亡率增加相关。与对照组相比，ATM和PTEN低表达阴性的患者总生存期降低且癌症死亡率增加。
