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 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; Anne E. Kiltie

doi:10.1038/ng.558

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, Anne E. Kiltie

The Rowett Institute of Nutrition and Health

University of Oxford

Research output: Contribution to journal › Article › peer-review

156 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 language	English
Pages (from-to)	415-419
Number of pages	5
Journal	Nature Genetics
Volume	42
Issue number	5
DOIs	https://doi.org/10.1038/ng.558
Publication status	Published - May 2010

Bibliographical note

Funding Information:
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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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., ... Kiltie, A. E. (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

Kiemeney, LA, Sulem, P, Besenbacher, S, Vermeulen, SH, Sigurdsson, A, Thorleifsson, G, Gudbjartsson, DF, Stacey, SN, Gudmundsson, J, Zanon, C, Kostic, J, Masson, G, Bjarnason, H, Palsson, ST, Skarphedinsson, OB, Gudjonsson, SA, Witjes, JA, Grotenhuis, AJ, Verhaegh, GW, Bishop, DT, Sak, SC, Choudhury, A, Elliott, F, Barrett, JH, Hurst, CD, De Verdier, PJ, Ryk, C, Rudnai, P, Gurzau, E, Koppova, K, Vineis, P, Polidoro, S, Guarrera, S, Sacerdote, C, Campagna, M, Placidi, D, Arici, C, Zeegers, MP, Kellen, E, Gutierrez, BS, Sanz-Velez, JI, Sanchez-Zalabardo, M, Valdivia, G, Garcia-Prats, MD, Hengstler, JG, Blaszkewicz, M, Dietrich, H, Ophoff, RA, Van Den Berg, LH & Kiltie, AE 2010, 'A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer', Nature Genetics, vol. 42, no. 5, pp. 415-419. https://doi.org/10.1038/ng.558

@article{fc6611b22f61465a85385f2b30ededdc,

title = "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.",

author = "Kiemeney, {Lambertus A.} and Patrick Sulem and Soren Besenbacher and Vermeulen, {Sita H.} and Asgeir Sigurdsson and Gudmar Thorleifsson and Gudbjartsson, {Daniel F.} and Stacey, {Simon N.} and Julius Gudmundsson and Carlo Zanon and Jelena Kostic and Gisli Masson and Hjordis Bjarnason and Palsson, {Stefan T.} and Skarphedinsson, {Oskar B.} and Gudjonsson, {Sigurjon A.} and Witjes, {J. Alfred} and Grotenhuis, {Anne J.} and Verhaegh, {Gerald W.} and Bishop, {D. Timothy} and Sak, {Sei Chung} and Ananya Choudhury and Faye Elliott and Barrett, {Jennifer H.} and Hurst, {Carolyn D.} and {De Verdier}, {Petra J.} and Charlotta Ryk and Peter Rudnai and Eugene Gurzau and Kvetoslava Koppova and Paolo Vineis and Silvia Polidoro and Simonetta Guarrera and Carlotta Sacerdote and Marcello Campagna and Donatella Placidi and Cecilia Arici and Zeegers, {Maurice P.} and Eliane Kellen and Gutierrez, {Berta Saez} and Sanz-Velez, {Jos{\'e} I.} and Manuel Sanchez-Zalabardo and Gabriel Valdivia and Garcia-Prats, {Maria D.} and Hengstler, {Jan G.} and Meinolf Blaszkewicz and Holger Dietrich and Ophoff, {Roel A.} and {Van Den Berg}, {Leonard H.} and Kiltie, {Anne E.}",

note = "Funding Information: We thank the individuals who participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE{\textquoteright}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 {\textquoteleft}Prinses Beatrix Fonds{\textquoteright}, 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:{\textquoteleft}Food Quality and Safety{\textquoteright} (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.",

year = "2010",

month = may,

doi = "10.1038/ng.558",

language = "English",

volume = "42",

pages = "415--419",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

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TY - JOUR

T1 - A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

AU - Kiemeney, Lambertus A.

AU - Sulem, Patrick

AU - Besenbacher, Soren

AU - Vermeulen, Sita H.

AU - Sigurdsson, Asgeir

AU - Thorleifsson, Gudmar

AU - Gudbjartsson, Daniel F.

AU - Stacey, Simon N.

AU - Gudmundsson, Julius

AU - Zanon, Carlo

AU - Kostic, Jelena

AU - Masson, Gisli

AU - Bjarnason, Hjordis

AU - Palsson, Stefan T.

AU - Skarphedinsson, Oskar B.

AU - Gudjonsson, Sigurjon A.

AU - Witjes, J. Alfred

AU - Grotenhuis, Anne J.

AU - Verhaegh, Gerald W.

AU - Bishop, D. Timothy

AU - Sak, Sei Chung

AU - Choudhury, Ananya

AU - Elliott, Faye

AU - Barrett, Jennifer H.

AU - Hurst, Carolyn D.

AU - De Verdier, Petra J.

AU - Ryk, Charlotta

AU - Rudnai, Peter

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - Vineis, Paolo

AU - Polidoro, Silvia

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Campagna, Marcello

AU - Placidi, Donatella

AU - Arici, Cecilia

AU - Zeegers, Maurice P.

AU - Kellen, Eliane

AU - Gutierrez, Berta Saez

AU - Sanz-Velez, José I.

AU - Sanchez-Zalabardo, Manuel

AU - Valdivia, Gabriel

AU - Garcia-Prats, Maria D.

AU - Hengstler, Jan G.

AU - Blaszkewicz, Meinolf

AU - Dietrich, Holger

AU - Ophoff, Roel A.

AU - Van Den Berg, Leonard H.

AU - Kiltie, Anne E.

N1 - Funding Information: 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.

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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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DO - 10.1038/ng.558

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SN - 1061-4036

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EP - 419

JO - Nature Genetics

JF - Nature Genetics

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

Abstract

Bibliographical note

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