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

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 × 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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Figure 1: Schematic view of the structure and association results in the UBC-associated region on chromosome 4p16.3.
Figure 2: Correlation between genotypes of rs798766 and the expression of FGFR3 and TACC3 in adipose tissue from 604 individuals.

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Acknowledgements

We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE's recruitment center and the personnel at the deCODE core facilities. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic UBC cases. C.Z. and S.B. are funded by a FP7-MC-IAPP Grant agreement no. 218071 (CancerGene). Collection of samples and data in Iceland and The Netherlands was funded in part by the European Commission (POLYGENE: LSHC-CT-2005) and a research investment grant of the Radboud University Nijmegen Medical Centre. Control samples for the Dutch follow-up group were genotyped with generous support from the 'Prinses Beatrix Fonds', VSB Fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, J.R. van Dijk and the Adessium foundation. The controls from the Dutch Schizophrenia GWA study were genotyped with the support of the US National Institute of Mental Health (R.A.O.). The Leeds Bladder Cancer Study was funded by Cancer Research UK and Yorkshire Cancer Research. The Torino Bladder Cancer Case Control Study was supported by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union Sixth Framework Program, Priority 5: 'Food Quality and Safety' (Contract No. 513943), and by grants of the Compagnia di San Paolo, of the Italian Association for Cancer Research and of the Piedmont Region Progetti de Ricerca Sanitaria Finalizzata, Italy. The Belgian case-control study on bladder cancer risk was supported by a grant of the Flemish government, the government of the Belgian province of Limburg and the Limburg Cancer Fund.

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Contributions

The study was designed and results were interpreted by L.A.K., P.S., U.T., M.A.K., T.R. and K.S. Statistical analysis was carried out by L.A.K., P.S., S.B., G.T., D.F.G., G. Masson and A.K. Subject ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by S.H.V., J.A.W., A.J.G., G.W.V., D.T.B., S.C.S., A.C., F.E., J.H.B., C.D.H., P.J.d.V., C.R., P.R., E.G., K. Koppova, P.V., S. Polidoro, S.G., C.S., M.C., D.P., C.A., M.P.Z., E.K., B.S.G., J.I.S.-V., M.S.-Z., G.V., M.D.G.-P., J.G.H., M.B., H.D., R.A.O., L.H.v.d.B., K.A., K. Kristjansson, G.G., S.N., V.P., N.A.M., A.L., M.A.v.E., S. Porru, F.B., K.G., J.I.M., R.K., G. Matullo, G.S., A.E.K., K.K.H.A., T.T., E.J. and M.A.K. Principal investigators for the UBC follow-up populations were A.E.K. (UK), G. Matullo and P.V. (Torino), S. Porru (Brescia), M.P.Z. and F.B. (Belgium), R.K. (Eastern Europe), J.I.M. (Spain), G.S. (Sweden), K.G. (Germany) and L.A.K. (The Netherlands, group 2). Genotyping and laboratory experiments were carried out by A.S., S.N.S., J.G., J.K., H.B., S.T.P., O.B.S. and C.D.H. Bioinformatics analysis was carried out by P.S., A.S., G.T., C.Z. and S.A.G. L.A.K., P.S., U.T., M.A.K., T.R. and K.S. drafted the manuscript. All authors contributed to the final version of the paper.

Corresponding authors

Correspondence to Lambertus A Kiemeney or Kari Stefansson.

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The authors from deCODE genetics are shareholders in deCODE Genetics Inc.

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Supplementary Note, Supplementary Tables 1–12 and Supplementary Figures 1 and 2 (PDF 1706 kb)

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Kiemeney, L., Sulem, P., Besenbacher, S. et al. A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nat Genet 42, 415–419 (2010). https://doi.org/10.1038/ng.558

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