A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer
Thorunn Rafnar and colleagues identify a variant on 4p16.3 near FGFR3 associated with increased risk of urinary bladder cancer. They find that the risk allele is more frequent among individuals with tumors that carry an activating somatic mutation in FGFR3 , suggesting a link between germline variat...
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| Published in | Nature genetics Vol. 42; no. 5; pp. 415 - 419 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.05.2010
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Thorunn Rafnar and colleagues identify a variant on 4p16.3 near
FGFR3
associated with increased risk of urinary bladder cancer. They find that the risk allele is more frequent among individuals with tumors that carry an activating somatic mutation in
FGFR3
, suggesting a link between germline variation, somatic mutation status and cancer risk.
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. |
|---|---|
| AbstractList | 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.sup.-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. 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 super(-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. 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. 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. 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.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. Thorunn Rafnar and colleagues identify a variant on 4p16.3 near FGFR3 associated with increased risk of urinary bladder cancer. They find that the risk allele is more frequent among individuals with tumors that carry an activating somatic mutation in FGFR3 , suggesting a link between germline variation, somatic mutation status and cancer risk. 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. 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^sup -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. [PUBLICATION ABSTRACT] |
| Audience | Academic |
| Author | Masson, Gisli Vermeulen, Sita H Thorleifsson, Gudmar Vineis, Paolo Mayordomo, José I Jonsson, Eirikur Kumar, Rajiv van Es, Michael A Campagna, Marcello Sanchez-Zalabardo, Manuel Gurzau, Eugene Koppova, Kvetoslava Dietrich, Holger Rafnar, Thorunn Barrett, Jennifer H Alexiusdottir, Kristin Choudhury, Ananya Stefansson, Kari Kostic, Jelena Lindblom, Annika Aben, Katja K H Buntinx, Frank Sigurdsson, Asgeir Ophoff, Roel A Sacerdote, Carlotta Porru, Stefano Gudmundsson, Julius Stacey, Simon N Blaszkewicz, Meinolf Geirsson, Gudmundur Matullo, Giuseppe Thorsteinsdottir, Unnur Hengstler, Jan G Sanz-Velez, José I Nikulasson, Sigfus Garcia-Prats, Maria D van den Berg, Leonard H Elliott, Faye Gudbjartsson, Daniel F Verhaegh, Gerald W Rudnai, Peter Skarphedinsson, Oskar B Kong, Augustine Valdivia, Gabriel Golka, Klaus Sulem, Patrick Guarrera, Simonetta Knowles, Margaret A Witjes, J Alfred Palsson, Stefan T Kiltie, Anne E Bjarnason, Hjordis Bishop, D Timothy Hurst, Carolyn D Kristjansson, Kristleifur Mungan, N Aydin Sak, Sei Chung Ryk, Charlotta Arici, Cec |
| AuthorAffiliation | 6 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK 18 Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK 13 Department of Epidemiology and Public Health, Imperial College, London, UK 20 Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium 38 Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain 15 Unit of Cancer Epidemiology, University of Torino, Torino, Italy 10 Environmental Health Centre, Cluj-Napoca, Romania 25 Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain 22 Division of Urology, San Jorge Hospital, Huesca, Spain 5 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK 33 Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland 1 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud Univers |
| AuthorAffiliation_xml | – name: 8 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden – name: 25 Division of Surgical Pathology, San Jorge Hospital, Huesca, Spain – name: 18 Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, UK – name: 36 Department of General Practice, Catholic University of Leuven, Leuven, Belgium – name: 2 Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands – name: 10 Environmental Health Centre, Cluj-Napoca, Romania – name: 40 Section of Clinical Cancer Epidemiology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden – name: 7 Christie Hospital National Health Service Foundation Trust, Manchester, UK – name: 20 Leuven University Centre for Cancer Prevention (LUCK), Leuven, Belgium – name: 27 Department of Urology, Paul Gerhardt Foundation, Lutherstadt Wittenberg, Germany – name: 42 Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford, UK – name: 11 State Health Institute, Banska Bystrica, Slovakia – name: 38 Division of Medical Oncology, University of Zaragoza, Zaragoza, Spain – name: 15 Unit of Cancer Epidemiology, University of Torino, Torino, Italy – name: 5 Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK – name: 6 Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James’s University Hospital, Leeds, UK – name: 30 Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands – name: 29 University of California Los Angeles Center for Neurobehavioral Genetics, Los Angeles, USA – name: 19 Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, Maastricht, The Netherlands – name: 43 Faculty of Medicine, University of Iceland, Reykjavik, Iceland – name: 24 Department of Urology, University of Zaragoza School of Medicine, Zaragoza, Spain – name: 35 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden – name: 13 Department of Epidemiology and Public Health, Imperial College, London, UK – name: 34 Department of Urology, Zonguldak Karaelmas University, Zonguldak, Turkey – name: 14 Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy – name: 17 Department of Experimental and Applied Medicine, Section of Occupational Medicine and Industrial Hygiene, University of Brescia, Brescia, Italy – name: 26 Leibniz Research Centre for Working Environment and Human Factors, Dortmund, Germany – name: 28 Department of Medical Genetics, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands – name: 22 Division of Urology, San Jorge Hospital, Huesca, Spain – name: 33 Department of Pathology, Landspitali–University Hospital, Reykjavik, Iceland – name: 16 Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino, Italy – name: 37 Department of General Practice, Maastricht University, Maastricht, The Netherlands – name: 23 Division of Urology, Hospital Clinico, Zaragoza, Spain – name: 31 Department of Medical Oncology, Landspitali–University Hospital, Reykjavik, Iceland – name: 32 Department of Urology, Landspitali–University Hospital, Reykjavik, Iceland – name: 3 Comprehensive Cancer Center East, Nijmegen, The Netherlands – name: 4 deCODE Genetics, Reykjavik, Iceland – name: 39 Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany – name: 1 Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands – name: 9 National Institute of Environmental Health, Budapest, Hungary – name: 21 Department of Medicine, University of Zaragoza, Zaragoza, Spain – name: 41 Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, The Sahlgrenska Academy, Gothenburg, Sweden – name: 12 Institute for Scientific Interchange (ISI) Foundation, Torino, Italy |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 AUTHOR 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. These authors contributed equally to this work. A full list of author affiliations appears at the end of the paper. |
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Oncol.200624366436711:CAS:528:DC%2BD28XovVSjsbc%3D10.1200/JCO.2005.05.1771 H Stefansson (BFng558_CR26) 2005; 37 A Kong (BFng558_CR15) 2008; 40 H Wallerand (BFng558_CR14) 2005; 26 MA Knowles (BFng558_CR2) 2006; 27 BFng558_CR8 DC Tomlinson (BFng558_CR17) 2005; 65 DC Tomlinson (BFng558_CR19) 2007; 213 BFng558_CR9 LA Kiemeney (BFng558_CR5) 2008; 40 C Billerey (BFng558_CR10) 2001; 158 T Rafnar (BFng558_CR7) 2009; 41 S Hernandez (BFng558_CR11) 2006; 24 JM van Oers (BFng558_CR28) 2005; 11 X Wu (BFng558_CR6) 2009; 41 JI Epstein (BFng558_CR27) 1998; 22 S Gretarsdottir (BFng558_CR22) 2003; 35 N Mantel (BFng558_CR24) 1959; 22 V Emilsson (BFng558_CR18) 2008; 452 A Kong (BFng558_CR16) 2009; 462 JW Catto (BFng558_CR21) 2009; 69 BFng558_CR1 KK Aben (BFng558_CR4) 2002; 98 D Cappellen (BFng558_CR20) 1999; 23 C Murta-Nascimento (BFng558_CR3) 2007; 16 B Devlin (BFng558_CR25) 1999; 55 CT Falk (BFng558_CR23) 1987; 51 AA Bakkar (BFng558_CR13) 2010; 49 TE Thorgeirsson (BFng558_CR12) 2008; 452 21414868 - Eur Urol. 2010 Dec;58(6):943-4. doi: 10.1016/j.eururo.2010.09.022. |
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| Snippet | Thorunn Rafnar and colleagues identify a variant on 4p16.3 near
FGFR3
associated with increased risk of urinary bladder cancer. They find that the risk allele... Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the... |
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| SubjectTerms | 631/208/69 631/208/727/2000 631/208/737 692/699/67/589/1336 Agriculture Alleles Animal Genetics and Genomics Biological and medical sciences Biomedical and Life Sciences Biomedicine Bladder cancer Cancer Cancer and Oncology Cancer och onkologi Cancer Research Chromosomes Chromosomes, Human, Pair 4 Disease-Free Survival Europe Female Fibroblast Growth Factor Fundamental and applied biological sciences. Psychology Gene Function Genetic Genetic aspects Genetic Predisposition to Disease Genetic susceptibility Genetic Variation genetics Genetics of eukaryotes. Biological and molecular evolution Genotype Human Human Genetics Humans letter Male Medical research Medical sciences Models, Genetic Mutation Nephrology. Urinary tract diseases Pair 4 Receptor Receptor, Fibroblast Growth Factor, Type 3 - genetics Recurrence Risk Risk factors Smoking Tumors Tumors of the urinary system Type 3 Urinary bladder Urinary Bladder Neoplasms Urinary Bladder Neoplasms - genetics Urinary system involvement in other diseases. Miscellaneous Urinary tract. Prostate gland |
| Title | A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer |
| URI | https://link.springer.com/article/10.1038/ng.558 https://www.ncbi.nlm.nih.gov/pubmed/20348956 https://www.proquest.com/docview/222682492 https://www.proquest.com/docview/733087181 https://www.proquest.com/docview/746234216 https://pubmed.ncbi.nlm.nih.gov/PMC2923020 https://gup.ub.gu.se/publication/134597 http://kipublications.ki.se/Default.aspx?queryparsed=id:120375072 |
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