These data demonstrate that in appropriately selected patients, endovascular repair of isolated iliac artery aneurysms is a safe, effective alternative to open repair with mid-term follow-up. Endovascular repair is associated with a significantly reduced hospital length of stay and may be associated with decreased need for transfusion and mortality when compared with open repair.
APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into “APOBEC-high” and “APOBEC-low” based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.
The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.
As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single or double- strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or following a latency period cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. While the application of PARP inhibitors (PARPis) was initially focused on tumors with BRCA1 or BRCA2 deficiency, our current knowledge has extended synthetic susceptibilities of PARPi to deficiencies in proteins and pathways involved in DNA damage repair (DDR) in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder, and especially prostate cancers, contain subsets of patients with germline and somatic alterations in HR genes that may reflect increased response to PARPis. In this review, we describe the mechanisms and rationale of PARPi use in GU cancers, summarize previously reported pre-clinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can be applied for widespread application in GU cancers.
What's known on the subject? and What does the study add? There have been several studies that have suggested there may be a relationship between prostate biopsy and erectile function and LUTS. Previous studies have suggested a specific association between the type of local anaesthesia administered and/or the number of biopsies performed. Other studies have suggested an exacerbation of LUTS after prostate biopsy. The present study identifies a positive cancer diagnosis as a novel characteristic that may explain a relationship between biopsy and worsening erectile function. Objective To evaluate prospectively the characteristics, erectile function and lower urinary tract symptoms (LUTS) of men undergoing prostate needle biopsy (PNBx). Patients and Methods From 2008 to 2011, 134 men were prospectively administered the International Index of Erectile Function (IIEF), American Urological Association Symptom Index (AUA‐SI), and quality‐of‐life (QoL) questionnaires before and after undergoing a single 12‐core PNBx. Comparisons of IIEF and AUA‐SI scores before and after PNBx, based upon baseline characteristics and prostate cancer (PCa) diagnosis, were performed. Univariable and multivariable logistic regression models were used to characterize predictors of change in IIEF scores. Results In the 85 men who fulfilled the inclusion criteria, there were no significant differences between the mean (sd) total pre‐biopsy and the mean (sd) post‐biopsy IIEF scores: 57.8 (12.9) vs 54.3 (17.2). Subgroup analysis showed that men who had biopsy‐proven PCa had significantly greater changes in their post‐biopsy IIEF scores compared with men without (−10.1 vs. 1.0; P < 0.001). After specific analyses of the IIEF domains in these groups we found significant decreases in every domain, including erectile function (P = 0.01). On multivariate analyses, only PCa diagnosis was associated with a significant change in IIEF (odds ratio 7.2; P = 0.003). There were no differences in AUA‐SI or QoL scores in the overall population or in subgroups. Conclusions Cancer diagnosis appears to have an adverse effect on the erectile function of men undergoing PNBx but no effect on LUTS. This study highlights a potential negative psychological confounder that may influence erectile function before the treatment of PCa. Additional prospective trials evaluating these relationships are warranted.
BackgroundThe APOBEC family of enzymes is responsible for a mutation signature characterized by a TCW>T/G mutation. APOBEC-mediated mutagenesis is implicated in a wide variety of tumors, including bladder cancer. In this study, we explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival. We hypothesized that tumors with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and associated with higher expression of genes related to activation of the immune system.MethodsGene expression (n=408) and mutational (n=395) data from the Cancer Genome Atlas (TCGA) bladder urothelial carcinoma provisional dataset was utilized for analysis. Tumors were split into “APOBEC-high” and “APOBEC-low” tumors based on APOBEC enrichment score. Analysis was performed with R.FindingsPatients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs 18.5 months, p=0.005). Tumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2), and chromatin regulatory genes (MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with total mutational burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis and enrichment is associated with increased expression of immune-related genes, including interferon signaling.InterpretationTumors enriched for APOBEC mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, potentially providing more single-strand DNA substrate for APOBEC3A and APOBEC3B, leading to a hypermutational phenotype and the subsequent immune response.HighlightsABPOEC enzymes, particularly APOBEC3A and APOBEC3B, are responsible for the predominant pattern of mutagenesis in bladder cancerTumors enriched for APOBEC-mediated mutagenesis are more likely to have mutations in DNA damage response genes and chromatin regulatory genes, while tumors not enriched for APOBEC-mediated mutagenesis are more likely to have mutations in KRAS and FGFR3APOBEC enrichment is associated with upregulation of genes involved in the immune response
Urine collections from patients during metabolic evaluation for nephrolithiasis may be considered inadequate based on two commonly used clinical definitions. This may have therapeutic or economic ramifications and the propensity for females to supply inadequate samples should be investigated further.
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