A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

Kiemeney, Lambertus A.; Sulem, Patrick; Besenbacher, Søren; Vermeulen, Sita H.; Sigurðsson, Ásgeir; Þorleifsson, Guðmar; Guðbjartsson, Daníel F.; Stacey, Simon; Guðmundsson, Jūlı́us; Zanon, Carlo; Kostic, Jelena; Másson, Gísli; Bjarnason, Hjördis; Palsson, Stefan; Skarphedinsson, Oskar B; Gudjonsson, Sigurjon A.; Witjes, J. Alfred; Grotenhuis, Anne J.; Verhaegh, Gerald W.; Bishop, D. Timothy; Sak, Sei Chung; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer; Hurst, Carolyn D.; Verdier, Petra J. de; Ryk, Charlotta; Rudnai, Péter; Gurzău, Eugen; Koppová, Kvetoslava; Víneis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Campagna, Marcello; Placidi, Donatella; Arici, Cecilia; Zeegers, Maurice P.; Kellen, Eliane; Gutierrez, Berta Saez; Sanz-Velez, José I; Sanchez-Zalabardo, Manuel; Valdivia, Gabriel; García-Prats, María Dolores; Hengstler, Jan G.; Blaszkewicz, Meinolf; Dietrich, H.; Ophoff, Roel A.; Berg, Leonard H. van den; Alexíusdóttir, Kristín; Kristjánsson, Kristleifur; Geirsson, Guðmundur; Nikulásson, Sigfús; Pétursdóttir, Vigdís; Kong, Augustine; Thorgeirsson, Thorgeir E.; Mungan, N.A.; Lindblom, Annika; Es, Michael A. van; Porru, Stefano; Buntinx, Frank; Golka, Klaus; Mayordomo, J. I.; Kumar, Rajiv; Matullo, Giuseppe; Steineck, Gunnar; Kiltie, Anne E.; Aben, Katja K.H.; Jónsson, Eiríkur; Þorsteinsdóttir, Unnur; Knowles, Margaret A.; Rafnar, Thorunn; Stefánsson, Kāri

doi:10.1038/ng.558

Cited by 161 publications

(110 citation statements)

References 26 publications

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“…There is some precedent supporting the notion of individual susceptibility to mutation development in the case of JAK2 in leukemia (53,54). Recently, a genome-wide association study in patients with bladder cancer showed that a SNP located in 4p16, in the vicinity of FGFR3, is associated with somatic FGFR3 mutations in tumors (55). However, this study did not address the issue of multicentricity that we analyzed in detail here.…”

Section: Discussioncontrasting

confidence: 44%

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Hafner

Toll

Fernández-Casado

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.

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Section: Discussioncontrasting

confidence: 44%

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Hafner

Toll

Fernández-Casado

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Disturbances of centrosome function have also been implicated in tumorigenesis (Zyss and Gergely, 2009). Intriguingly, aberrations of TACC3 expression are associated with the etiology of ovarian, bladder and non-small-cell lung cancer (Lauffart et al, 2005;Jung et al, 2006;Kiemeney et al, 2010). Moreover, we have recently shown that the cellular outcome of mitotic stress induced by TACC3 depletion is decisively determined by the status of the post-mitotic G 1 checkpoint.…”

Section: Introductionmentioning

confidence: 99%

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

et al. 2010

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Microtubule-interfering cancer drugs such as paclitaxel (PTX) often cause chemoresistance and severe side effects, including neurotoxicity. To explore potentially novel antineoplastic molecular targets, we investigated the cellular response of breast carcinoma cells to short hairpin(sh)RNA-mediated depletion of the centrosomal protein transforming acidic coiled coil (TACC) 3, an Aurora A kinase target expressed during mitosis. Unlike PTX, knockdown of TACC3 did not trigger a cell death response, but instead resulted in a progressive loss of the pro-apoptotic Bcl-2 protein Bim that links microtubule integrity to spindle poison-induced cell death. Interestingly, TACC3-depleted cells arrested in G 1 through a cellular senescence program characterized by the upregulation of nuclear p21 WAF , downregulation of the retinoblastoma protein and extracellular signal-regulated kinase 1/2, formation of HP1c (phospho-Ser83)-positive senescence-associated heterochromatic foci and increased senescence-associated b-galactosidase activity. Remarkably, the onset of senescence following TACC3 knockdown was strongly accelerated in the presence of non-toxic PTX concentrations. Thus, we conclude that mitotic spindle stress is a major trigger of premature senescence and propose that the combined targeting of the centrosomal Aurora A-TACC3 axis together with drugs interfering with microtubule dynamics may efficiently improve the chemosensitivity of cancer cells.

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“…[2][3][4][5][6][7][8][9] The SNPs rs9642880 at 8q24.21 and rs710521 at 3q28 were the first to be identified as common susceptibility loci for bladder cancer in nine study groups of European ancestry.…”

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confidence: 99%

“…1 Several significant GWAS of bladder cancer have provided strong evidence for over 10 independent loci and single-nucleotide polymorphisms (SNPs) that reach the statistical genome-wide significance. [2][3][4][5][6][7][8][9] The SNPs rs9642880 at 8q24.21 and rs710521 at 3q28 were the first to be identified as common susceptibility loci for bladder cancer in nine study groups of European ancestry. 2 The second SNP rs2294008 at 8q24.3 harboring PSCA, an adjunct marker for the detection of urothelial transitional cell carcinoma, has subsequently been identified by a GWAS in US and European populations.…”

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confidence: 99%

Cumulative effect of genome‐wide association study‐identified genetic variants for bladder cancer

Wang

Chu

Lv³

et al. 2014

Intl Journal of Cancer

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Recent genome-wide association studies have identified 14 genetic variants associated with bladder cancer in Caucasians. The effects of these risk variants and their cumulative effects in Asian populations are unknown. We genotyped these newly identified variants in a case-control study of 1,050 patients diagnosed with bladder cancer and 1,404 controls in the Chinese population. Odds rations (ORs) and 95% confidence intervals (CIs) were computed by logistic regression, and cumulative effect of risk alleles were evaluated. Overall, seven of the 14 variants were significantly associated with bladder cancer risk (p 5 9.763 3 10 23 for rs9642880 at 8q24.21, p 5 3.004 3 10 23 for rs2294008 at 8q24.3, p 5 0.012 for rs798766 at 4p16.3, p 5 0.034 for rs1495741 at 8p22, p 5 2.306 3 10 24 for GSTM1, p 5 8.507 3 10 28 for rs17674580 at 18q12.3, p 5 7.179 3 10 24 for rs10936599 at 3q26.2) and the odds ratios (ORs) ranged from 1.13 to 1.65. Moreover, there were a significant increased risk for bladder cancer positively correlated numbers of risk alleles and smoking status (P trend 5 7.060 3 10 216). However, no allelic interaction effects on bladder cancer risk were observed between cumulative effects of variants and clinical characteristics. These findings suggest that seven bladder cancer risk-associated variants (rs9642880, rs2294008, rs798766, rs1495741, GSTM1 null, rs17674580 and rs10936599) may be used, collectively, to effectively measure inherited risk for bladder cancer.Recent advances in human genomics, especially the genomewide association studies (GWAS), have improved the effectiveness of the discover of genetic variants underlying complex diseases, including bladder cancer.1 Several significant GWAS of bladder cancer have provided strong evidence for over 10 independent loci and single-nucleotide polymorphisms (SNPs) that reach the statistical genome-wide significance. [2][3][4][5][6][7][8][9] The SNPs rs9642880 at 8q24.21 and rs710521 at 3q28 were the first to be identified as common susceptibility loci for bladder cancer in nine study groups of European ancestry.2 The second SNP rs2294008 at 8q24.3 harboring PSCA, an adjunct marker for the detection of urothelial transitional cell carcinoma, has subsequently been identified by a GWAS in US and European populations.3 Then additional Epidemiology

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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

Cited by 161 publications

References 26 publications

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program

Cumulative effect of genome‐wide association study‐identified genetic variants for bladder cancer

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