Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease

Simon R Walker; Ramy Abdelsalam; Sunita Ghosh; Julie Livingstone; Nallasivam Palanisamy; Paul C Boutros; Steven M Yip; Susan P Lees-Miller; Tarek A Bismar

doi:10.1016/j.euros.2021.05.004

Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease

Eur Urol Open Sci. 2021 Jun 12:29:93-101. doi: 10.1016/j.euros.2021.05.004. eCollection 2021 Jul.

Authors

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Calgary Cumming School of Medicine and Alberta Precision Laboratories, Calgary, AB, Canada.
² Department of Medical Oncology, Faculty of Medicine and Dentistry, University of Alberta, and Alberta Health Services-Cancer Control, Edmonton, AB, Canada.
³ Departments of Human Genetics and Urology, University of California, Los Angeles, CA, USA.
⁴ Department of Urology, Vattikuti Urology Institute, Henry Ford Health System Detroit, MI, USA.
⁵ Tom Baker Cancer Centre, Calgary, AB, Canada.
⁶ Departments of Oncology, Biochemistry and Molecular Biology, University of Calgary Cumming School of Medicine, Calgary, AB, Canada.
⁷ Arnie Charbonneau Cancer Institute, Calgary, AB, Canada.

Abstract

Background: 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).

Objective: To investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status.

Design setting and participants: This study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP).

Outcome measurements and statistical analysis: 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).

Results and limitations: Decreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 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, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups.

Conclusions: 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.

Patient summary: 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.

Keywords: ATM; Androgen deprivation therapy; Cancer-specific mortality; ERG; Gleason score; Immunohistochemistry; Overall survival; PTEN; Poly-ADP ribose polymerase and ATR inhibitors; Protein expression.

Grants and funding

P50 CA211015/CA/NCI NIH HHS/United States