Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

Association of CYP1B1 L432V polymorphism with urinary cancer susceptibility: a meta-analysis.

BACKGROUND: The Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates. Previous studies have reported the existence of CYP1B1 L432V missense polymorphism in prostate, bladder and renal cancers. However, the effects of this polymorphism on the risk of these cancers remain conflicting. Therefore, we performed a meta-analysis to assess the association between L432V polymorphism and the susceptibility of urinary cancers. METHODS: We searched the PubMed database without limits on language for studies exploring the relationship of CYP1B1 L432V polymorphism and urinary cancers. Article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of these associations. Simultaneously, publication bias was estimated by funnel plot and Begg's test with Stata 11 software. RESULTS: We observed a significant association between CYP1B1 L432V polymorphism and urinary cancers. The overall OR (95% CI) of CC versus CG was 0.937 (0.881-0.996), the overall OR (95% CI) of CC versus CG+GG was 0.942 (0.890-0.997). Furthermore, we identified reduced risk for CC versus other phenotypes in both prostate and overall urinary cancers, when studies were limited to Caucasian or Asian patients. CONCLUSIONS: This meta-analysis suggests that the CYP1B1 L432V polymorphism is associated with urinary cancer risk. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3108829721231527.

Prognostic role of NLR in urinary cancers: a meta-analysis.

BACKGROUND: Recently, many studies explored the role of inflammation parameters such as neutrophil-to-lymphocyte ratio (NLR) in the prognosis of urinary cancers, but the results were not consistent. METHODS: We carried out a meta-analysis of published studies to assess the prognostic value of NLR in patients with urinary cancers. Hazard ratio (OR) with 95% confidence interval (CI) was used to assess the association of NLR and OS and RFS/CSS. RESULTS: The pooled results showed that high NLR was a poor predictor for OS with HR of 1.81 (95%CI: 1.48-2.21; Pheterogeneity = 0.005) and RFS/CSS (HR = 2.07, 95% CI: 1.65-2.6; Pheterogeneity = 0.849). Subgroup analyses revealed that high NLR yielded a worse OS in RCC (HR = 1.9, 95%CI: 1.47-2.45; Pheterogeneity = 0.003) and a poor RFS/CSS in RCC (HR = 1.83, 95%CI: 1.35-2.48; Pheterogeneity = 0.709), bladder cancer (HR = 2.2, 95%CI: 1.27-3.8; Pheterogeneity = 0.447) and urothelial carcinoma (HR = 2.58, 95%CI: 1.66-4.01; Pheterogeneity = 0.784). CONCLUSION: Our results showed that NLR could act as a significant biomarker in the prognosis of urinary cancers.

Distinguishing characteristics of urothelial carcinoma in kidney transplant recipients between China and Western countries.

OBJECTIVE: To identify significant distinctive characteristics of urothelial carcinoma (UC) in kidney transplant recipients between China and Western countries and investigate probable tumor screening and treatment factors contributing to these differences. METHODS: Renal transplant recipients from 1998 to 2011 in our institution diagnosed with UC were included in this study. Our data on tumor incidence, clinical characteristics, and outcomes were compared with literature reports. RESULTS: Among 2572 renal transplant recipients identified, 24 (0.93%) experienced UC, including 10 men and 14 women of overall mean age of 49.3 ± 11.6 years at transplantation and 53.5 ± 9.5 years at tumor detection. The Chinese traditional herbal intake mainly focused on 2 preparations: Aristolochic acid and rhubarb (the latter was mainly used in patients with chronic renal impairment) in 20 people. There were 21 (87.5%) cases of upper (UTUC) 5 cases of bilateral, and 13 cases of multifocal urinary tract urothelial carcinoma. Four subjects died owing to tumor progression at 4-63 months postoperatively. CONCLUSIONS: UC in renal transplant recipients shared notable characteristics in China with widespread herb intake: UTUC predominance; multifocal and bilateral organ involvement; high rates of recurrence, progression, and dissemination, in contrast with bladder tumor dominance in Western countries. As a consequence, we suggest that bilateral nephroureterectomy should be performed prophylactically in high-risk patients, especially those with a long history of Chinese herb intake. The relationship of rhubarb consumption to UC in renal transplant recipients should be noted and evaluated.

Diabetes and urothelial cancer risk: the Multiethnic Cohort study.

BACKGROUND: It is important to understand the adverse health sequelae that may result from the rising incidence of diabetes. Diabetics may have an increased risk for urothelial cancer but the evidence from prospective studies and ethnically diverse populations is sparse. METHOD: We examined this association in the Multiethnic Cohort (MEC) that was conducted in Hawaii and Los Angeles with nearly 186,000 participants in five ethnic groups. Over a median 10.7 years of follow-up, 918 incident cases of urothelial cancer (89% bladder and 11% other urinary tract sites) were identified through tumor registry linkages. RESULTS: A self-reported diagnosis of diabetes was associated with an increased risk of urothelial cancer (relative risk=1.25; 95% confidence interval: 1.04-1.50). The association was not explained by body mass index, physical activity, or smoking. There was some suggestion that the risk was higher in women, Whites and African Americans, and past smokers. The risk associated with diabetes for in situ and localized cancer was similar to that for regional and distant cancer. CONCLUSION: This study demonstrates that the increased urothelial cancer risk with diabetes in this multiethnic population is very similar to that observed in mostly White or Asian populations. Whether or not the elevated risk is moderated by the degree of control of the hyperglycemia associated with diabetes will need to be determined in future studies.

Cancers of the urinary tract among American Indians and Alaska Natives in the United States, 1999-2004.

BACKGROUND: Assessment of the kidney parenchyma ("kidney") and urinary bladder ("bladder") cancer burden among American Indians and Alaska Natives (AI/AN) has been limited. Using a database with improved classification for AI/AN, the authors described patterns of these 2 cancers among AI/AN and non-Hispanic whites (NHW) in the United States. METHODS: Cases diagnosed during 1999 to 2004 were identified through National Program of Cancer Registries and the Surveillance, Epidemiology and End Results program and linked to the Indian Health Service (IHS) registration records. Age-adjusted incidence rates, rate ratios (RR), annual percent change, and stage at diagnosis were stratified by IHS Contract Health Service Delivery Area (CHSDA) counties to adjust for misclassification. RESULTS: Kidney cancer incidence among AI/AN in CHSDA counties exceeded that among NHW (RR, 1.51; 95% confidence interval [CI], 1.42-1.61), and was highest among AI/AN in the Northern Plains, Southern Plains, Alaska, and Southwest. Average annual increases were highest among AI/AN (5.9%) and NHW (5.9%) males aged 20 to 49 years, although statistically significant only among NHW. Conversely, bladder cancer incidence was significantly lower among AI/AN than NHW (RR, 0.40; 95% CI, 0.37-0.44). For both sites, AI/AN were significantly less likely to be diagnosed at an earlier stage than NHW. CONCLUSIONS: AI/AN have about 50% greater risk of kidney cancer and half the risk of bladder cancer than NHW. Although reasons for these enigmatic patterns are not known, sustained primary prevention efforts through tobacco cessation and obesity prevention are warranted.

Upper urinary tract urothelial carcinoma in eastern Taiwan: high proportion among all urothelial carcinomas and correlation with chronic kidney disease.

BACKGROUND/PURPOSE: This study investigated the incidence of upper urinary tract urothelial carcinoma (UUT-UC) in eastern Taiwan and its association with chronic kidney disease (CKD). METHODS: A total of 110 patients with histologically proven UUT-UC over a recent 20-year period were retrospectively analyzed to determine the clinical profile, overall survival and correlation with CKD. RESULTS: The mean age at diagnosis was 68.7 +/- 9.8 years (range, 43-93 years), and the male to female ratio was 1 to 1.16 (51:59). The ratio of urothelial carcinoma (UC) of the renal pelvis to UC of the ureter to UC of the bladder was 1.2:1:6.7. UC of the renal pelvis accounted for 10.8% of all urinary tract UC, and for 41% of all renal cancer detected during the study period. The 2-, 5- and 10-year cancer-specific survival rates of patients with UUT-UC were 75%, 53.0% and 29%, respectively. Patients with high grade and high stage UUT-UC had significantly worse prognosis than those with low grade (p = 0.0047) and low stage (p = 0.0021). Of the 110 patients, 64 (58%) had impaired renal function (glomerular filtration rate < 60 mL/min/1.73 m2; defined as CKD), including 14 (13%) with end-stage renal disease (ESRD) before diagnosis. Patients with CKD or ESRD had significantly worse prognosis than those with normal renal function (p = 0.0399). High grade UC was found in 35 of 58 patients with CKD or ESRD (60%), which was significantly higher than in patients with normal renal function (12/26, 26%; p = 0.019). CONCLUSION: A high proportion of UUT-UC was observed among all UCs and a significantly higher percentage of high grade UUT-UC (60%) were found in patients with CKD or ESRD in eastern Taiwan. These findings suggest that CKD and ESRD might play a role in the development of UC especially in the upper urinary tract.

Urothelial cancer in white and Japanese patients in Hawaii: pathology.

The sites, growth patterns, histological grades and degrees of invasion of urothelial tumors were assessed among white and Japanese patients in Hawaii. Tissues were available from 225 white and 164 Japanese patients, representing virtually all of the urothelial tumors from these races entered into the Hawaii Tumor Registry for Oahu island between 1977 and 1986. No statistically significant interracial differences emerged from the analysis. Grade 1 papillary tumors were the most numerous types encountered, consisting of 43% of the urothelial tumors in men of both races, and 37.5% in white and 31% in Japanese women. Recently, observed increasing incidence trends of urothelial tumors among white men in the United States are associated with a synchronous decrease in mortality trends. Our analysis indicates that these diverging trends cannot be accounted for by increased numbers of noninvasive papillary tumors.