Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

被引：30

作者：

Figueroa, Jonine D. ^{[1
,2
]}

Middlebrooks, Candace D. ^{[1
]}

Banday, A. Rouf ^{[1
]}

Ye, Yuanqing ^{[3
]}

Garcia-Closas, Montserrat ^{[1
,5
]}

Chatterjee, Nilanjan ^{[1
]}

Koutros, Stella ^{[1
]}

Kiemeney, Lambertus A. ^{[6
]}

Rafnar, Thorunn ^{[7
]}

Bishop, Timothy ^{[8
]}

Furberg, Helena ^{[10
]}

Matullo, Giuseppe ^{[14
,15
]}

Golka, Klaus ^{[16
]}

Gago-Dominguez, Manuela ^{[17
]}

Taylor, Jack A. ^{[18
,19
]}

Fletcher, Tony ^{[20
]}

Siddiq, Afshan ^{[21
]}

Cortessis, Victoria K. ^{[23
,24
,25
]}

Kooperberg, Charles ^{[26
]}

Cussenot, Olivier ^{[27
,30
,31
]}

Benhamou, Simone ^{[32
,33
]}

Prescott, Jennifer ^{[34
,35
,36
]}

Porru, Stefano ^{[39
]}

Dinney, Colin P. ^{[4
]}

Malats, Nuria ^{[40
]}

Baris, Dalsu ^{[1
]}

Purdue, Mark P. ^{[1
]}

Jacobs, Eric J. ^{[41
]}

Albanes, Demetrius ^{[1
]}

Wang, Zhaoming ^{[42
]}

Chung, Charles C. ^{[1
,4
]}

Vermeulen, Sita H. ^{[6
]}

Aben, Katja K. ^{[6
]}

Galesloot, Tessel E. ^{[6
]}

Thorleifsson, Gudmar ^{[7
]}

Sulem, Patrick ^{[7
]}

Stefansson, Kari ^{[7
,43
,44
]}

Kiltie, Anne E.

Harland, Mark ^{[8
]}

Teo, Mark ^{[9
]}

Offit, Kenneth ^{[11
]}

Vijai, Joseph ^{[11
]}

Bajorin, Dean ^{[12
]}

Kopp, Ryan ^{[13
]}

Fiorito, Giovanni ^{[14
,15
]}

Guarrera, Simonetta ^{[14
,15
]}

Sacerdote, Carlotta ^{[45
]}

Selinski, Silvia ^{[16
]}

Hengstler, Jan G. ^{[16
]}

Gerullis, Holger ^{[46
,47
]}

机构：

[1] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[2] Univ Edinburgh, Inst Genet & Mol Med, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland

[3] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Urol, Houston, TX 77030 USA

[5] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England

[6] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Hlth Sci, NL-6525 ED Nijmegen, Netherlands

[7] Amgen Inc, deCODE Genet, Reykjavik, Iceland

[8] Univ Leeds, Epidemiol & Biostat Sect, Leeds LS9 7TF, W Yorkshire, England

[9] Univ Leeds, Leeds Inst Canc & Pathol, Radiotherapy Res Grp, Leeds LS9 7TF, W Yorkshire, England

[10] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, 1275 York Ave, New York, NY 10021 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Genitourinary Oncol Serv, 1275 York Ave, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Dept Surg, Urol Serv, 1275 York Ave, New York, NY 10021 USA

[14] Univ Turin, Dept Med Sci, Turin, Italy

[15] Human Genet Fdn, Turin, Italy

[16] Leibniz Res Ctr Working Environm & Human Factor, Dortmund, Germany

[17] Inst Invest Sanit Santiago IDIS, Serv Galego Saude SERGAS, Galician Fdn Genom Med, Genom Med Grp, Santiago De Compostela, Spain

[18] NIEHS, Epidemiol Branch, POB 12233, Res Triangle Pk, NC 27709 USA

[19] NIEHS, Epigenet & Stem Cell Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA

[20] London Sch Hyg & Trop Med, London WC1, England

[21] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England

[22] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC, PHE Ctr Environm & Hlth, London, England

[23] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[24] Univ So Calif, Dept Obstet & Gynecol, Los Angeles, CA 90089 USA

[25] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA

[26] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[27] Tenon, Dept Urol, Paris, France

[28] Pitie Salpetriere, Dept Urol, Paris, France

[29] Pitie Salpetriere, AP HP, Dept Pathol, Paris, France

[30] Ctr Rech Pathol Prostat, Paris, France

[31] Univ Paris 06, ONCOTYPE URO, GRC 5, Paris, France

[32] Fdn Jean Dausset Ctr Etud Polymorphisme Humain CE, INSERM, U946, Paris, France

[33] Inst Gustave Roussy, UMR8200, Ctr Natl Rech Sci, Villejuif, France

[34] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 75 Francis St, Boston, MA 02115 USA

[35] Harvard Univ, Sch Med, Boston, MA 02115 USA

[36] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA

[37] Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA

[38] Harvard Univ, Sch Publ Hlth, Dept Biostat, 665 Huntington Ave, Boston, MA 02115 USA

[39] Univ Brescia, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth, Brescia, Italy

[40] Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain

[41] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA

[42] Natl Canc Inst, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD USA

[43] Univ Iceland, Fac Med, Reykjavik, Iceland

[44] Univ Oxford, Dept Oncol, CRUK MRC Oxford Inst Radiat Oncol, Old Rd Campus,Res Bldg,Roosevelt Dr, Oxford OX3 7DQ, England

[45] CPO Piemonte, Canc Epidemiol, Turin, Italy

[46] Carl von Ossietzky Univ Oldenburg, Sch Med & Hlth Sci, Klinikum Oldenburg, Univ Hosp Urol, D-26111 Oldenburg, Germany

[47] Lukasklin Neuss, Dept Urol, Neuss, Germany

[48] St Josefs Hosp, Dept Urol, Dortmund, Germany

[49] Xerencia Xest Integrada Vigo SERGAS, Inst Invest Biomed IBI Orense Pontevedra Vigo, Oncol & Genet Unit, Complejo Hosp, Vigo, Spain

[50] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Galicia, Spain

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 06期

关键词：

GENOME-WIDE ASSOCIATION; NUCLEOTIDE EXCHANGE FACTOR; NAT2 SLOW ACETYLATION; CONFERS SUSCEPTIBILITY; SEQUENCE VARIANT; GSTM1; NULL; SMOKING; SLC14A1; GENE; RHO;

D O I：

10.1093/hmg/ddv492

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1x 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 x 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 x 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P <= 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

引用

页码：1203 / 1214

页数：12

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