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

L.A. Kiemeney, P. Sulem, S. Besenbacher, S.H. Vermeulen, A. Sigurdsson, G. Thorleifsson, D.F. Gudbjartsson, S.N. Stacey, J. Gudmundsson, C. Zanon, J. Kostic, G. Masson, H. Bjarnason, S.T. Palsson, O.B. Skarphedinsson, S.A. Gudjonsson, J.A. Witjes, A.J. Grotenhuis, G.W. Verhaegh, D.T. BishopS.C. Sak, A. Choudhury, F. Elliott, J.H. Barrett, C.D. Hurst, P.J. de Verdier, C. Ryk, P. Rudnai, E. Gurzau, K. Koppova, P. Vineis, S. Polidoro, S. Guarrera, C. Sacerdote, M. Campagna, D. Placidi, C. Arici, M.P.A. Zeegers, E. Kellen, B.S. Gutierrez, J.I. Sanz Velez, M. Sanchez Zalabardo, G. Valdivia, M.D. Garcia Prats, J.G. Hengstler, M. Blaszkewicz, H. Dietrich, R.A. Ophoff, L.H. van den Berg, K. Alexiusdottir, K. Kristjansson, G. Geirsson, S. Nikulasson, V. Petursdottir, A. Kong, T. Thorgeirsson, N.A. Mungan, A. Lindblom, M.A. van Es, S. Porru, F.J.V.M. Buntinx, K. Golka, J.I. Mayordomo, R. Kumar, G. Matullo, G. Steineck, A.E. Kiltie, K.K. Aben, E. Jonsson, U. Thorsteinsdottir, M.A. Knowles, T. Rafnar, K. Stefansson

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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.
Original languageEnglish
Pages (from-to)415-419
Number of pages7
JournalNature Genetics
Volume42
Issue number5
DOIs
Publication statusPublished - May 2010

Keywords

  • UROTHELIAL CELL-CARCINOMA
  • FGFR3 MUTATIONS
  • DISEASE
  • RISK
  • EXPRESSION

Cite this

Kiemeney, L. A., Sulem, P., Besenbacher, S., Vermeulen, S. H., Sigurdsson, A., Thorleifsson, G., Gudbjartsson, D. F., Stacey, S. N., Gudmundsson, J., Zanon, C., Kostic, J., Masson, G., Bjarnason, H., Palsson, S. T., Skarphedinsson, O. B., Gudjonsson, S. A., Witjes, J. A., Grotenhuis, A. J., Verhaegh, G. W., ... Stefansson, K. (2010). A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer. Nature Genetics, 42(5), 415-419. https://doi.org/10.1038/ng.558