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

Lambertus A. Kiemeney, 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 BishopSei 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

Research output: Article

128 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)415-419
Number of pages5
JournalNature genetics
Volume42
Issue number5
DOIs
Publication statusPublished - máj. 1 2010

ASJC Scopus subject areas

  • Genetics

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    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