Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3

Wang, Meilin; Li, Zhiqiang; Chu, Haiyan; Lv, Qiang; Ye, Dingwei; Ding, Qiang; Xu, Chuanliang; Guo, Jianming; Du, Mulong; Chen, Jianhua; Song, Zhijian; Chen, Yin; Qin, Chao; Gu, Chengyuan; Zhu, Yao; Xia, Guowei; Liu, Fang; Zhang, Zhengsheng; Lin, Yuan; Fu, Guangbo; Hu, Zhibin; Tong, Na; Shen, Jiawei; Liu, Ke; Sun, Jielin; Sun, Yinghao; Li, Jue; Li, Xingwang; Shen, Hongbing; Xu, Jianfeng; Shi, Yongyong; Zhang, Zhengdong

doi:10.1158/0008-5472.can-15-2564

Cited by 43 publications

(41 citation statements)

References 40 publications

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“…After filtering, we identified 4 common variants and 11 lowfrequency and rare variants that were significantly associated with bladder cancer risk. In addition, we also genotyped additional 11 SNVs that were in previous reported GWA studies (21). Finally, 26 SNVs were selected for further validation in the additional cohorts.…”

Section: Exome Array Analysismentioning

confidence: 99%

“…Genome-wide association studies (GWAS) have identified 17 independent loci and single nucleotide variants (SNVs) that contribute to bladder cancer susceptibility in European population [(8-14); Table S1]. Many loci have been replicated in additional studies, and additional new loci found to be, associated with bladder cancer risk in Chinese population (15)(16)(17)(18)(19)(20)(21). GWA studies have been successful in identifying common variants involved in complex trait etiology.…”

Section: Introductionmentioning

confidence: 99%

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The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population

Wang

Chen

et al. 2020

Front. Oncol.

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Background: Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. However, little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population. Methods:We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome-array data in 1,019 bladder cancer patients and 1,008 controls in discovery stage. Two replication stages were included to validate variants identified. Bonferroni adjustment was performed to define statistical significance. Logistic regression was conducted to evaluate single marker association with bladder cancer risk. We used SKAT-O method to perform gene level-based analysis. We also conduct additional experiments to explore the underlying mechanism of filtered gene(s). Results:We identified a novel rare coding variant (rs35356162 in UHRF1BP1: G > T, OR = 4.332, P = 3.62E-07 < 7.93E-07, Bonferroni cutoff) that increased bladder cancer risk in Han Chinese. Gene-level analysis showed a significant association of UHRF1BP1 (P = 4.47E-03) with bladder cancer risk. Experiments indicated down-regulation of UHRF1BP1 promoted migration and invasion through epithelial-mesenchymal transition in bladder cancer cell lines. Conclusion:The rare variant of UHRF1BP1, rs35356162, increases bladder cancer risk in Han Chinese and UHRF1BP1 might act as a tumor suppressor in bladder cancer development and progression.

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Section: Exome Array Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population

Wang

Chen

et al. 2020

Front. Oncol.

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“…In addition to family history, heritable genetic variants associated with BCa have been discovered. For example, more than 20 common single nucleotide polymorphisms have been reported in genome‐wide association studies . Rare germline genetic variants with high penetrance, however, have not been systematically evaluated.…”

Section: Introductionmentioning

confidence: 99%

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

Jiang

et al. 2018

BJU International

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“…Rs2042329 ( CWC27 ) was linked to an increased risk of UBC recurrence (OR = 1.26, 95% CI: 1.10; 1.48); while rs804256, rs4639, and rs804276, all located in/close to NEIL2 were associated with NMIBC-only recurrence (OR = 1.23, 95% CI: 1.05–1.43; OR = 1.20, 95%CI: 1.03–1.39; OR = 1.17, 95% CI: 1.01–1.36, respectively). All SNPs that were associated with recurrence showed consistent direction, but were more modest in comparison to the original studies [HR = 1.54 (1.10–2.16) for rs2042329 (12), HR = 4.58 (2.61–8.02) for rs804256 (13), HR = 2.60 (1.68–4.03) for rs4639 (13), and HR = 2.71 (1.75–4.20) for rs804276 (13)].…”

Section: Resultsmentioning

confidence: 85%

External Replication of Urinary Bladder Cancer Prognostic Polymorphisms in the UK Biobank

et al. 2019

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Introduction: Multiple studies have reported genetic associations with prognostic outcomes of urinary bladder cancer. However, the lack of replication of these associations prohibits establishing further evidence-based research directions. Moreover, there is a lack of independent bladder cancer patient samples that contain prognostic measures, making genetic replication analyses even more challenging.Materials and Methods: We have identified 1,534 eligible patients and used data on Hospital Episode Statistics in the UK Biobank to model variables of otherwise non-collected events on bladder cancer recurrence and progression. Data on survival was extracted from the Death Registry. We have used SNPTEST software to replicate previously reported genetic associations with bladder cancer recurrence (N = 69), progression (N = 23), survival (N = 53), and age at the time of diagnosis (N = 20).Results: Using our algorithm, we have identified 618 recurrence and 58 UBC progression events. In total, there were 209 deaths (106 UBC-specific). In replication analyses, eight SNPs have reached nominal statistical significance (p < 0.05). Rs2042329 (CWC27) for UBC recurrence; rs804256, rs4639, and rs804276 (in/close to NEIL2) for NMIBC recurrence; rs2293347 (EGFR) for UBC OS; rs3756712 (PDCD6) for NMIBC OS; rs2344673 (RGS5) for MIBC OS, and rs2297518 (NOS2) for UBC progression. However, none have remained significant after adjustments for multiple comparisons.Discussion: External replication in genetic epidemiology is an essential step to identify credible findings. In our study, we identify potential genetic targets of higher interest for UBC prognosis. In addition, we propose an algorithm for identifying UBC recurrence and progression using routinely-collected data on patient interventions.

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Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3

Cited by 43 publications

References 40 publications

The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population

The Rare Variant rs35356162 in UHRF1BP1 Increases Bladder Cancer Risk in Han Chinese Population

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

External Replication of Urinary Bladder Cancer Prognostic Polymorphisms in the UK Biobank

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