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

• Published in: Nature genetics Vol. 42; no. 5; pp. 415 - 419
• Main Authors: Geirsson, Gudmundur, Hengstler, Jan G, Kostic, Jelena, Grotenhuis, Anne J, Thorsteinsdottir, Unnur, Sanchez-Zalabardo, Manuel, Jonsson, Eirikur, Skarphedinsson, Oskar B, Witjes, J Alfred, Kellen, Eliane, Gutierrez, Berta Saez, Sanz-Velez, José I, Vermeulen, Sita H, Gurzau, Eugene, Mungan, N Aydin, Gudmundsson, Julius, Verhaegh, Gerald W, Bjarnason, Hjordis, Thorleifsson, Gudmar, Kong, Augustine, Steineck, Gunnar, Alexiusdottir, Kristin, Vineis, Paolo, van Es, Michael A, Mayordomo, José I, Sigurdsson, Asgeir, Zanon, Carlo, Lindblom, Annika, Elliott, Faye, Buntinx, Frank, Gudjonsson, Sigurjon A, Golka, Klaus, Sacerdote, Carlotta, Ryk, Charlotta, Placidi, Donatella, Valdivia, Gabriel, Thorgeirsson, Thorgeir, Masson, Gisli, Petursdottir, Vigdis, Sak, Sei Chung, van den Berg, Leonard H, Knowles, Margaret A, Matullo, Giuseppe, Aben, Katja K H, de Verdier, Petra J, Rudnai, Peter, Kiltie, Anne E, Kiemeney, Lambertus A, Porru, Stefano, Polidoro, Silvia, Palsson, Stefan T, Bishop, D Timothy, Stacey, Simon N, Blaszkewicz, Meinolf, Besenbacher, Soren, Guarrera, Simonetta, Hurst, Carolyn D, Garcia-Prats, Maria D, Kumar, Rajiv, Ophoff, Roel A, Gudbjartsson, Daniel F, Campagna, Marcello, Barrett, Jennifer H, Rafnar, Thorunn, Nikulasson, Sigfus, Arici, Cecilia, Koppova, Kvetoslava, Dietrich, Holger, Kristjansson, Kristleifur, Stefansson, Kari, Sulem, Patrick, Zeegers, Maurice P, Choudhury, Ananya
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2010; Nature Publishing Group
• Subjects: 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; Medicin och hälsovetenskap; 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; Europe; United Kingdom; Germany; Spain; Variant; Urinary system disease; Bladder disease; Urinary tract disease; Malignant tumor; Bladder cancer; Cancer
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.558

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.