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

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.

Identification of Candidate lncRNA and Pseudogene Biomarkers Associated with Carbon-Nanotube-Induced Malignant Transformation of Lung Cells and Prediction of Potential Preventive Drugs

“…Knockdown of CLU was verified to significantly promote the growth of lung cancer cells in vitro and in vivo [ 64 ]. A decreased expression level of ATM was associated with inferior OS and higher prostate cancer-specific mortalities [ 65 ]. Activation of the ATM/checkpoint kinase 2/p53-dependent signaling pathway was shown to inhibit the chemoresistance of HGC-27 cells to oxaliplatin [ 66 ].…”

Genomic analysis across 53 canine cancer types reveals novel mutations and high clinical actionability potential

“…Furthermore, exploring the interactions between co‐occurring genes can guide the development of combination therapies targeting multiple genes or pathways. For example, it is known that the frequent co‐occurrence of ATM ‐ PTEN mutations in human prostate cancer have substantial implications for prognosis, treatment strategies, and clinical outcomes, 47 which could be applicable to the 74 tumours in our cohort that exhibit the same co‐occurrence. Similarly, the simultaneous presence of APC and TP53 gene mutations in colorectal cancer is known to serve as a diagnostic signature 48 .…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes

“…PTEN activity may be also reduced in PC; its expression can lack in whole tumor or in some areas [ 10 , 19 , 38 , 53 , 77 , 86 , 96 ]. PTEN loss is a relatively frequent, late event in mCRPCs, which is probably associated with worse prognosis [ 197 , 204 , 205 ]; however, it may indicate a sensitivity to Akt-inhibitors (such as ipatasertib) [ 200 , 206 ].…”