DNA Repair Pathway Alterations in Bladder Cancer

Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways—including the double-strand break (DSB) and nucleotide excision repair (NER) pathways—are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy. In addition, tumor DNA repair defects have important implications for use of immunotherapy and other targeted agents in bladder cancer. Therefore, efforts to further understand the landscape of DNA repair alterations in bladder cancer will be critical in advancing treatment for bladder cancer. This review summarizes the current understanding of the role of DNA repair pathway alterations in bladder tumor biology and response to therapy

Relative Timing of Radiotherapy and Androgen Deprivation for Prostate Cancer and Implications for Treatment During the COVID-19 Pandemic

This cohort study uses National Cancer Database data from 2004 to 2014 to examine the association between overall survival and timing of radiotherapy relative to androgen deprivation therapy in patients with prostate cancer

Doublecortin Expression in Prostate Adenocarcinoma and Neuroendocrine Tumors

Recent work using prostate cancer mouse models implicated doublecortin (DCX)-expressing neural progenitor cells in prostate adenocarcinoma, reporting a strong association between DCX expression and histologic grade and clinical outcome. We sought to evaluate the relationship between DCX expression and these variables in human prostate cancer. DCX expression was measured in transcriptome-wide microarray data from 18,501 patients with localized prostate cancer and 290 patients with metastatic castration-resistant prostate cancer (mCRPC) and compared across disease states, histologic grades, and clinical outcomes. Biochemical recurrence-free survival (BRFS), metastasis-free survival (MFS), and overall survival (OS) were analyzed using Cox proportional hazards. DCX expression was not significantly different among normal prostate (n = 29), primary prostate cancer (n = 131), and metastases (n = 19) and did not increase with grade in a large cohort of radical prostatectomy samples (n = 17,967). Those with DCX expression above and below the median did not have significant differences in BRFS (HR 1.15 [95% confidence interval, 0.88-1.49], P = .31), MFS (HR 1.2 [0.84-1.7], P = .3), or OS (HR 1.15 [0.7-1.84], P = .56). In a cohort with untreated prostate cancer, DCX expression was higher in neuroendocrine tumors (n = 10) compared with grade group 5 prostate adenocarcinoma (n = 110) (P = .007). Similarly, in 2 cohorts with mCRPC (n = 290), DCX expression was higher in lesions with neuroendocrine features compared with adenocarcinoma (P < .001). Contrary to recent data using mouse models, DCX expression did not differ by disease state or outcome and did not increase with grade in a large data set of patients with prostate adenocarcinoma. However, DCX expression appeared to correlate with neuroendocrine histology, a subgroup that can arise de novo or in the castrate-resistant setting. Further work is needed to define the role of DCX and its clinical significance in prostate cancer

Orchestrating serine resolvases

A remarkable feature of the serine resolvases is their regulation: the wild-type enzymes will catalyse intra- but not inter-molecular recombination, can sense the relative orientation of their sites and can exchange strands directionally, despite the fact that there is no net release of chemical bond energy. The key to this regulation is that they are only active within a large intertwined complex called the 'synaptosome'. Because substrate topology greatly facilitates (or, in other cases, inhibits) formation of the synaptosome, it acts as a 'topological filter'. Within the defined topology of the synaptosome, strand exchange releases supercoiling tension, providing an energy source to bias the reaction direction. The regulatory portion of this complex contains additional copies of the recombinase and sometimes other DNA-bending proteins. We are using a combination of X-ray crystallography, biochemistry and genetics to model the full synaptic complex and to understand how the regulatory portion activates the crossover-site-bound recombinase