A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer - PubMed (original) (raw)

doi: 10.1038/ng.558. Epub 2010 Mar 28.

Patrick Sulem, Soren Besenbacher, Sita H Vermeulen, Asgeir Sigurdsson, Gudmar Thorleifsson, Daniel F Gudbjartsson, Simon N Stacey, Julius Gudmundsson, Carlo Zanon, Jelena Kostic, Gisli Masson, Hjordis Bjarnason, Stefan T Palsson, Oskar B Skarphedinsson, Sigurjon A Gudjonsson, J Alfred Witjes, Anne J Grotenhuis, Gerald W Verhaegh, D Timothy Bishop, Sei Chung Sak, Ananya Choudhury, Faye Elliott, Jennifer H Barrett, Carolyn D Hurst, Petra J de Verdier, Charlotta Ryk, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Paolo Vineis, Silvia Polidoro, Simonetta Guarrera, Carlotta Sacerdote, Marcello Campagna, Donatella Placidi, Cecilia Arici, Maurice P Zeegers, Eliane Kellen, Berta Saez Gutierrez, José I Sanz-Velez, Manuel Sanchez-Zalabardo, Gabriel Valdivia, Maria D Garcia-Prats, Jan G Hengstler, Meinolf Blaszkewicz, Holger Dietrich, Roel A Ophoff, Leonard H van den Berg, Kristin Alexiusdottir, Kristleifur Kristjansson, Gudmundur Geirsson, Sigfus Nikulasson, Vigdis Petursdottir, Augustine Kong, Thorgeir Thorgeirsson, N Aydin Mungan, Annika Lindblom, Michael A van Es, Stefano Porru, Frank Buntinx, Klaus Golka, José I Mayordomo, Rajiv Kumar, Giuseppe Matullo, Gunnar Steineck, Anne E Kiltie, Katja K H Aben, Eirikur Jonsson, Unnur Thorsteinsdottir, Margaret A Knowles, Thorunn Rafnar, Kari Stefansson

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

Lambertus A Kiemeney et al. Nat Genet. 2010 May.

Abstract

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

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Figures

Figure 1

Figure 1

Schematic view of the structure and association results in the UBC-associated region on chromosome 4p16.3. (a) Pairwise correlation structure in an 800-kb interval (1.3–2.1 Mb, NCBI B35) on chromosome 4p16.3. The upper plot shows pairwise _D_’ for 292 common SNPs (with minor allele frequency > 5%) from the HapMap (v21) CEU dataset. The lower plot shows the corresponding _r_2 values. (b) Estimated recombination rates (saRR) in cM per Mb from the HapMap (v21) Phase II data. (c) Location of known genes in the region. (d) Schematic view of the association with bladder cancer for all SNPs tested in the region for the initial scan (Iceland and The Netherlands). The y axis shows the −log10 P value.

Figure 2

Figure 2

Correlation between genotypes of rs798766 and the expression of FGFR3 and TACC3 in adipose tissue from 604 individuals. (a) Expression of FGFR3. (b) Expression of TACC3. Expression is shown as 10(average MLR), where MLR is the mean log10 expression ratio and the average is taken over individuals with a particular genotype. Regression of the MLR values on the number of copies of the UBC risk variant rs798766[T] shows that the expression of FGFR3 is increased by an estimated 22.4% with each T allele carried, whereas the expression of TACC3 is increased by an estimated 9.1% with each allele. The effect of age and sex is taken into account in the regression by including the variables age, sex and the interaction of age × sex among the explanatory variables.

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