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Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.

ABSTRACT: Micro-RNAs (miRNAs) are small non-coding RNA molecules, which can act as either oncogenes or tumor suppressors. Dysregulated expression of miRNA genes have been implicated in the development of many different cancers. We hypothesize that genetic variations in miRNA biogenesis genes may be associated with the prognosis of bladder cancer. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis genes in 421 patients with non-muscle-invasive bladder cancer (NMIBC). We analyzed the associations of SNPs with recurrence and progression in all patients as well as stratified by treatment: transurethral resection (TUR) alone or TUR plus intravesical bacillus Calmette-Guérin (BCG) instillation. Two SNPs were significantly associated with tumor recurrence in TUR only subgroup after adjustment for multiple comparisons (Q < 0.1). The most significant SNP was rs197412 in DDX20: the variant allele conferred a decreased risk of recurrence [hazard ratio (HR) = 0.58, 95% confidence interval (95% CI) = 0.40-0.82]. This SNP was validated in a separate group of 586 NMIBC patients and the pooled HR was 0.62 (95% CI = 0.48-0.81, P < 0.001). Two linked SNPs (rs2073778 and rs720012) in DGCR8 showed significant association with tumor progression (HR = 4.00, 95% CI = 1.53-10.46, P = 0.005). A strong gene-dosage effect was observed with higher risk for tumor recurrence and progression with increasing number of unfavorable genotypes. Haplotype and survival tree analyses further characterized the association of miRNA-related SNPs with tumor recurrence and progression. Taken together, our results indicate that genetic variants in miRNA biogenesis pathway may influence bladder cancer clinical outcome in NMIBC patients.

SUBMITTER: Ke HL

PROVIDER: S-EPMC3643413 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.

Ke Hung-Lung HL Chen Meng M Ye Yuanqing Y Hildebrandt Michelle A T MA Wu Wen-Jeng WJ Wei Hua H Huang Maosheng M Chang David W DW Dinney Colin P CP Wu Xifeng X

Carcinogenesis 20130114 5

Micro-RNAs (miRNAs) are small non-coding RNA molecules, which can act as either oncogenes or tumor suppressors. Dysregulated expression of miRNA genes have been implicated in the development of many different cancers. We hypothesize that genetic variations in miRNA biogenesis genes may be associated with the prognosis of bladder cancer. We genotyped 76 single nucleotide polymorphisms (SNPs) in eight miRNA biogenesis genes in 421 patients with non-muscle-invasive bladder cancer (NMIBC). We analyz ...[more]

PMID: 23322153

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Project description:BACKGROUND:Bladder cancer (BC) has become a major worldwide public health issue, especially non-muscle-invasive bladder cancer (NMIBC). A flood of related clinical practice guidelines (CPGs) have emerged; however, the quality and recommendations of the guidelines are controversial. We aimed to appraise the quality of the CPGs for NMIBC within the past 5?years and compare the similarities and differences between recommendations for therapies. METHODS:A systematic search to identify CPGs for NMIBC was performed using electronic databases (including PubMed, Embase, Web of Science), guideline development organizations, and professional societies from January 12, 2014 to January 12, 2019. The Appraisal of Guidelines Research & Evaluation (AGREE) II instrument was used to evaluate the quality of the guidelines. Intraclass correlation coefficient (ICC) analysis was performed to assess the overall agreement among reviewers. RESULTS:Nine CPGs were included. The overall agreement among reviewers was excellent. The interquartile range (IQR) of scores for each domain were as follows: scope and purpose 69.44% (35.42, 85.42%); stakeholder involvement 41.67% (30.56, 75.00%); rigour of development 48.96% (27.08, 65.63%); clarity and presentation 80.56% (75.00, 86.11%); applicability 34.38% (22.92, 40.63%) and editorial independence 70.83% (35.42, 85.42%). The NICE, AUA, EAU and CRHA/CPAM clinical practice guidelines consistently scored well in most domains. It was generally accepted that the transurethral resection of bladder tumour (TURBT) and intravesical chemotherapy should be performed in the management of bladder cancer. The application of chemotherapy was highly controversial in high risk NMIBC. The courses of BCG maintenance were similar and included 3?years of therapy at full maintenance doses. CONCLUSIONS:The quality of NMIBC guidelines within the past 5?years varied, especially regarding stakeholders, rigour and applicability. Despite many similarities, the recommendations had some inconsistencies in the details.

Project description:BackgroundNon-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC.Methods and resultsWe used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97-1.00; CD8T: HR = 0.97, 95% CI = 0.95-1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00-1.07; mdNLR: HR = 1.12, 95% CI = 1.04-1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P < 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites.ConclusionsOur results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence.

Dataset Information

Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.

Publications

Genetic variations in micro-RNA biogenesis genes and clinical outcomes in non-muscle-invasive bladder cancer.

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