DNA-Damage-Repair Gene Alterations in Genitourinary Malignancies

Abstract

Background High-fidelity repair of DNA damage repair (DDR) [either single-strand- (SSBs) or double-strand breaks (DSBs)] is necessary for maintaining genomic integrity and cell survival. DDR alterations are commonly found in genito-urinary malignancies involving either DSBs repair by the homologous recombination repair (HRR) system (BRCA1/2 pathway) or the SSBs repair through the Poly-ADP-ribose polymerase (PARP) pathway. PARP inhibitors (PARPi) exploit defects in the DNA repair pathway through synthetic lethality, DSBs being repaired only in HR-proficient cells but not in HR-deficient (HRD) cells. Summary A growing body of evidence support the need for identification of germinal and somatic DDR alterations in patients with genito-urinary malignancies. PARPi have already shown significant survival benefits in patients harboring HRR mutations in advanced settings, paving the way for precision medicine. Key messages In advanced prostate cancer (PCa), somatic mutations in HRR pathway are observed in up to 27% of metastatic resistant-to-castration PCa (mCRPC), although occurring early in PCa development, and mainly involving BRCA2, ATM, CHEK2 and BRCA1. Overall, germinal alterations are present in roughly 30-50% of cases of HRR alterations, and relative risk of PCa in germinal BRCA2-alterations carriers is 4.65 fold higher compared to non-carriers. Determination of DDR gene status is recommended in metastatic patients, a fortiori in mCRPC setting, since it could be a putative biomarker of response to first-line of treatment [androgen-receptor signaling inhibitors (ARSI) versus taxane-base chemotherapy] and allows to assess eligibility for PARPi use. Thus, olaparib (combined with androgen deprivation therapy) recently improved overall survival in mCRPC HRD-patients, after new hormonal therapy (NHT) and led to its approvement for patients with an alteration in 14 of 15 prespecified HRR genes. Moreover, since pre-clinical data suggested synergic action between PARPi and ARSI, the use of either olaparib or niraparib has also been proposed in combination with NHT, with a radiological progression-free survival improvement when used with abiraterone. In urothelial carcinoma, a DDR gene alteration is identified in 23-54% of patients mostly in muscle-invasive bladder cancer, with a strong association between DDR gene mutation and a higher tumor mutation burden and sensitivity to cisplatin-based chemotherapy and immunotherapy. Recent phase 2 trials supported the use of HRR status to select patients for PARPi treatment in advanced urothelial carcinoma. Finally, in renal cell carcinomas (RCC), pathogenic germline variants in DDR genes were identified in 7.3% of the cases, and deleterious somatic alterations have also been described as recurrent genomic events in patients with advanced RCC.

Effect of silencing SSB1 gene on the expression of NBS1 in irradiated rat submandibular gland cells

“…The genes of cells are continuously destroyed due to DNA damage [36]. In the lifetime of a cell, naturally occurring DNA damage continues, resulting in SSBs or DSBs [37]. Exogenous factors include IR, UV, and environmental chemicals, and endogenous factors include reactive oxygen species, incorrect DNA replication, accidental ribozyme cleavage, metabolic intermediates [28], erroneous DNA replication, and collapse.…”

Recent Research Advances in Double-Strand Break and Mismatch Repair Defects in Prostate Cancer and Potential Clinical Applications

“…Moreover, alterations in the ATM gene are associated with improved overall survival in PC patients treated with olaparib [33]. However, in mCRPC patients treated with olaparib, there was no objective radiological response, in contrast to BRCA1/2 patients [145]. Interestingly, ATM alterations were correlated with better outcomes to cisplatin-based chemotherapy in patients with mCRPC, compared to mCRPC with CDK12 defects [146].…”

Latin American Consensus for the Evaluation and Treatment of Patients With Metastatic/Locally Advanced Urothelial Carcinoma

“…Further studies are necessary to confirm these observations. 77 Other new therapies being explored for use in bladder cancer are drugs targeting the androgen receptor (AR), which through different pathways has been linked to the progression and response of this type of cancer. Preclinical studies have shown that AR inhibition in monotherapy can successfully inhibit the growth of urothelial carcinoma and it has a synergistic effect with cisplatin-based chemotherapy.…”