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Human Genetics

, Volume 131, Issue 7, pp 1095–1103 | Cite as

Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)

  • Guangfu Jin
  • Lingyi Lu
  • Kathleen A. Cooney
  • Anna M. Ray
  • Kimberly A. Zuhlke
  • Ethan M. Lange
  • Lisa A. Cannon-Albright
  • Nicola J. Camp
  • Craig C. Teerlink
  • Liesel M. FitzGerald
  • Janet L. Stanford
  • Kathleen E. Wiley
  • Sarah D. Isaacs
  • Patrick C. Walsh
  • William D. Foulkes
  • Graham G. Giles
  • John L. Hopper
  • Gianluca Severi
  • Ros Eeles
  • Doug Easton
  • Zsofia Kote-Jarai
  • Michelle Guy
  • Antje Rinckleb
  • Christiane Maier
  • Walther Vogel
  • Geraldine Cancel-Tassin
  • Christophe Egrot
  • Olivier Cussenot
  • Stephen N. Thibodeau
  • Shannon K. McDonnell
  • Daniel J. Schaid
  • Fredrik Wiklund
  • Henrik Grönberg
  • Monica Emanuelsson
  • Alice S. Whittemore
  • Ingrid Oakley-Girvan
  • Chih-Lin Hsieh
  • Tiina Wahlfors
  • Teuvo Tammela
  • Johanna Schleutker
  • William J. Catalona
  • S. Lilly Zheng
  • Elaine A. OstranderEmail author
  • William B. IsaacsEmail author
  • Jianfeng XuEmail author
  • International Consortium for Prostate Cancer Genetics
Original Investigation

Abstract

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families.

Keywords

Risk Allele Population Stratification 8q24 Region Shrimp Alkaline Phosphatase iPLEX 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

We would like to express our gratitude to the many families who participated in the studies involved in the International Consortium for Prostate Cancer Genetics (ICPCG). The ICPCG, including the consortium’s Data Coordinating Center (DCC), is made possible by a grant from the National Institutes of Health U01 CA89600 (to William B. Isaacs). Additional support to participating groups, or members within groups, is as follows: University of Utah Group: The authors appreciate the support of the University of Utah Huntsman Cancer Institute (to Lisa A. Cannon-Albright). FHCRC/NHGRI Group: Partial support was provided by the Fred Hutchinson Cancer Research Center (to Janet L. Stanford) and National Human Genome Research Institute (to Elaine A. Ostrander). ACTANE Group: We appreciate the support of the CR-UK grant A8385 and the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and Royal Marsden NHS Foundation Trust (to Ros Eeles), and Cancer Research UK (to Doug Easton). University of Umeå Group: Partial support was provided by the Swedish Cancer Society and a Spear grant from the Umeå University Hospital, Umeå, Sweden (to Henrik Grönberg). University of Tampere Group: We appreciate the support of the Competitive Research Funding of the Pirkanmaa Hospital District (9L091), Reino Lahtikari Foundation, Finnish Cancer Organisations, Sigrid Juselius Foundation and Academy of Finland (116437 and 126714) (to Johanna Schleutker). Northwestern University Group: Partial support was provided from Robert H. Lurie Comprehensive Cancer Center and the Urological Research Foundation (to William J. Catalona). University of Michigan Group: Partial support was provided by NIH P50 CA69568, NIH R01 CA79596 (to Kathleen Cooney), and the University of Michigan Comprehensive Cancer Center. Data Coordinating Center: Partial support was provided by NCI CA119069 and CA129684 (to Jianfeng Xu). We also thank other investigators who contributed to this work: ACTANE Group: Daniel Leongamornlert, Ed Saunders, Malgorzata Tymrakiewicz, Lynne O’Brien, Emma Sawyer, Rosemary Wilkinson, and Stephen Edwards from The Institute of Cancer Research, Sutton, Surrey. University of Ulm Group: Manuel Luedeke and Mark Schrader from Department of Urology, University of Ulm, Germany; Josef Hoegel and Christian Kubisch from Institute of Human Genetics, University of Ulm, Germany; and Kathleen Herkommer from Department of Urology, Technical University of Munich, Germany.

References

  1. Amundadottir LT, Sulem P, Gudmundsson J, Helgason A, Baker A, Agnarsson BA, Sigurdsson A, Benediktsdottir KR, Cazier JB, Sainz J, Jakobsdottir M, Kostic J, Magnusdottir DN, Ghosh S, Agnarsson K, Birgisdottir B, Le Roux L, Olafsdottir A, Blondal T, Andresdottir M, Gretarsdottir OS, Bergthorsson JT, Gudbjartsson D, Gylfason A, Thorleifsson G, Manolescu A, Kristjansson K, Geirsson G, Isaksson H, Douglas J, Johansson JE, Balter K, Wiklund F, Montie JE, Yu X, Suarez BK, Ober C, Cooney KA, Gronberg H, Catalona WJ, Einarsson GV, Barkardottir RB, Gulcher JR, Kong A, Thorsteinsdottir U, Stefansson K (2006) A common variant associated with prostate cancer in European and African populations. Nat Genet 38:652–658. doi: 10.1038/ng1808 PubMedCrossRefGoogle Scholar
  2. Duggan D, Zheng SL, Knowlton M, Benitez D, Dimitrov L, Wiklund F, Robbins C, Isaacs SD, Cheng Y, Li G, Sun J, Chang BL, Marovich L, Wiley KE, Balter K, Stattin P, Adami HO, Gielzak M, Yan G, Sauvageot J, Liu W, Kim JW, Bleecker ER, Meyers DA, Trock BJ, Partin AW, Walsh PC, Isaacs WB, Gronberg H, Xu J, Carpten JD (2007) Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J Natl Cancer Inst 99:1836–1844. doi: 10.1093/jnci/djm250 PubMedCrossRefGoogle Scholar
  3. Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, Mulholland S, Leongamornlert DA, Edwards SM, Morrison J, Field HI, Southey MC, Severi G, Donovan JL, Hamdy FC, Dearnaley DP, Muir KR, Smith C, Bagnato M, Ardern-Jones AT, Hall AL, O’Brien LT, Gehr-Swain BN, Wilkinson RA, Cox A, Lewis S, Brown PM, Jhavar SG, Tymrakiewicz M, Lophatananon A, Bryant SL, Horwich A, Huddart RA, Khoo VS, Parker CC, Woodhouse CJ, Thompson A, Christmas T, Ogden C, Fisher C, Jamieson C, Cooper CS, English DR, Hopper JL, Neal DE, Easton DF (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40:316–321. doi: 10.1038/ng.90 PubMedCrossRefGoogle Scholar
  4. Gudmundsson J, Sulem P, Manolescu A, Amundadottir LT, Gudbjartsson D, Helgason A, Rafnar T, Bergthorsson JT, Agnarsson BA, Baker A, Sigurdsson A, Benediktsdottir KR, Jakobsdottir M, Xu J, Blondal T, Kostic J, Sun J, Ghosh S, Stacey SN, Mouy M, Saemundsdottir J, Backman VM, Kristjansson K, Tres A, Partin AW, Albers-Akkers MT, Godino-Ivan Marcos J, Walsh PC, Swinkels DW, Navarrete S, Isaacs SD, Aben KK, Graif T, Cashy J, Ruiz-Echarri M, Wiley KE, Suarez BK, Witjes JA, Frigge M, Ober C, Jonsson E, Einarsson GV, Mayordomo JI, Kiemeney LA, Isaacs WB, Catalona WJ, Barkardottir RB, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K (2007a) Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39:631–637. doi: 10.1038/ng1999 PubMedCrossRefGoogle Scholar
  5. Gudmundsson J, Sulem P, Steinthorsdottir V, Bergthorsson JT, Thorleifsson G, Manolescu A, Rafnar T, Gudbjartsson D, Agnarsson BA, Baker A, Sigurdsson A, Benediktsdottir KR, Jakobsdottir M, Blondal T, Stacey SN, Helgason A, Gunnarsdottir S, Olafsdottir A, Kristinsson KT, Birgisdottir B, Ghosh S, Thorlacius S, Magnusdottir D, Stefansdottir G, Kristjansson K, Bagger Y, Wilensky RL, Reilly MP, Morris AD, Kimber CH, Adeyemo A, Chen Y, Zhou J, So WY, Tong PC, Ng MC, Hansen T, Andersen G, Borch-Johnsen K, Jorgensen T, Tres A, Fuertes F, Ruiz-Echarri M, Asin L, Saez B, van Boven E, Klaver S, Swinkels DW, Aben KK, Graif T, Cashy J, Suarez BK, van Vierssen Trip O, Frigge ML, Ober C, Hofker MH, Wijmenga C, Christiansen C, Rader DJ, Palmer CN, Rotimi C, Chan JC, Pedersen O, Sigurdsson G, Benediktsson R, Jonsson E, Einarsson GV, Mayordomo JI, Catalona WJ, Kiemeney LA, Barkardottir RB, Gulcher JR, Thorsteinsdottir U, Kong A, Stefansson K (2007b) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39:977–983. doi: 10.1038/ng2062 PubMedCrossRefGoogle Scholar
  6. Haiman CA, Patterson N, Freedman ML, Myers SR, Pike MC, Waliszewska A, Neubauer J, Tandon A, Schirmer C, McDonald GJ, Greenway SC, Stram DO, Le Marchand L, Kolonel LN, Frasco M, Wong D, Pooler LC, Ardlie K, Oakley-Girvan I, Whittemore AS, Cooney KA, John EM, Ingles SA, Altshuler D, Henderson BE, Reich D (2007) Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39:638–644. doi: 10.1038/ng2015 PubMedCrossRefGoogle Scholar
  7. Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360:1759–1768. doi: 10.1056/NEJMra0808700 PubMedCrossRefGoogle Scholar
  8. Laird NM, Horvath S, Xu X (2000) Implementing a unified approach to family-based tests of association. Genet Epidemiol 19 Suppl 1: S36-42. doi:  10.1002/1098-2272(2000)19:1+<::AID-GEPI6>3.0.CO;2-M
  9. Lange EM, Sun J, Lange LA, Zheng SL, Duggan D, Carpten JD, Gronberg H, Isaacs WB, Xu J, Chang BL (2008) Family-based samples can play an important role in genetic association studies. Cancer Epidemiol Biomarkers Prev 17:2208–2214. doi: 10.1158/1055-9965 PubMedCrossRefGoogle Scholar
  10. Lunetta KL, Faraone SV, Biederman J, Laird NM (2000) Family-based tests of association and linkage that use unaffected sibs, covariates, and interactions. Am J Hum Genet 66:605–614. doi: 10.1086/302782 PubMedCrossRefGoogle Scholar
  11. Manolio TA (2010) Genomewide association studies and assessment of the risk of disease. N Engl J Med 363:166–176. doi: 10.1056/NEJMra0905980 PubMedCrossRefGoogle Scholar
  12. Price AL, Zaitlen NA, Reich D, Patterson N (2010) New approaches to population stratification in genome-wide association studies. Nat Rev Genet 11:459–463. doi: 10.1038/nrg2813 PubMedCrossRefGoogle Scholar
  13. Salinas CA, Kwon E, Carlson CS, Koopmeiners JS, Feng Z, Karyadi DM, Ostrander EA, Stanford JL (2008) Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 17:1203–1213. doi: 10.1158/1055-9965.EPI-07-2811 PubMedCrossRefGoogle Scholar
  14. Schaid DJ, Chang BL (2005) Description of the International Consortium for Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. Prostate 63:276–290. doi: 10.1002/pros.20198 PubMedCrossRefGoogle Scholar
  15. Sun J, Lange EM, Isaacs SD, Liu W, Wiley KE, Lange L, Gronberg H, Duggan D, Carpten JD, Walsh PC, Xu J, Chang BL, Isaacs WB, Zheng SL (2008a) Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients. Prostate 68:489–497. doi: 10.1002/pros.20695 PubMedCrossRefGoogle Scholar
  16. Sun J, Zheng SL, Wiklund F, Isaacs SD, Purcell LD, Gao Z, Hsu FC, Kim ST, Liu W, Zhu Y, Stattin P, Adami HO, Wiley KE, Dimitrov L, Li T, Turner AR, Adams TS, Adolfsson J, Johansson JE, Lowey J, Trock BJ, Partin AW, Walsh PC, Trent JM, Duggan D, Carpten J, Chang BL, Gronberg H, Isaacs WB, Xu J (2008b) Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat Genet 40:1153–1155. doi: 10.1038/ng.214 PubMedCrossRefGoogle Scholar
  17. Thomas G, Jacobs KB, Yeager M, Kraft P, Wacholder S, Orr N, Yu K, Chatterjee N, Welch R, Hutchinson A, Crenshaw A, Cancel-Tassin G, Staats BJ, Wang Z, Gonzalez-Bosquet J, Fang J, Deng X, Berndt SI, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cussenot O, Valeri A, Andriole GL, Crawford ED, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hayes RB, Hunter DJ, Chanock SJ (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40:310–315. doi: 10.1038/ng.91 PubMedCrossRefGoogle Scholar
  18. Witte JS (2007) Multiple prostate cancer risk variants on 8q24. Nat Genet 39:579–580. doi: 10.1038/ng0507-579 PubMedCrossRefGoogle Scholar
  19. Xu J, Dimitrov L, Chang BL, Adams TS, Turner AR, Meyers DA, Eeles RA, Easton DF, Foulkes WD, Simard J, Giles GG, Hopper JL, Mahle L, Moller P, Bishop T, Evans C, Edwards S, Meitz J, Bullock S, Hope Q, Hsieh CL, Halpern J, Balise RN, Oakley-Girvan I, Whittemore AS, Ewing CM, Gielzak M, Isaacs SD, Walsh PC, Wiley KE, Isaacs WB, Thibodeau SN, McDonnell SK, Cunningham JM, Zarfas KE, Hebbring S, Schaid DJ, Friedrichsen DM, Deutsch K, Kolb S, Badzioch M, Jarvik GP, Janer M, Hood L, Ostrander EA, Stanford JL, Lange EM, Beebe-Dimmer JL, Mohai CE, Cooney KA, Ikonen T, Baffoe-Bonnie A, Fredriksson H, Matikainen MP, Tammela T, Bailey-Wilson J, Schleutker J, Maier C, Herkommer K, Hoegel JJ, Vogel W, Paiss T, Wiklund F, Emanuelsson M, Stenman E, Jonsson BA, Gronberg H, Camp NJ, Farnham J, Cannon-Albright LA, Seminara D (2005) A combined genomewide linkage scan of 1, 233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 77:219–229. doi: 10.1086/432377 PubMedCrossRefGoogle Scholar
  20. Yeager M, Orr N, Hayes RB, Jacobs KB, Kraft P, Wacholder S, Minichiello MJ, Fearnhead P, Yu K, Chatterjee N, Wang Z, Welch R, Staats BJ, Calle EE, Feigelson HS, Thun MJ, Rodriguez C, Albanes D, Virtamo J, Weinstein S, Schumacher FR, Giovannucci E, Willett WC, Cancel-Tassin G, Cussenot O, Valeri A, Andriole GL, Gelmann EP, Tucker M, Gerhard DS, Fraumeni JF Jr, Hoover R, Hunter DJ, Chanock SJ, Thomas G (2007) Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39:645–649. doi: 10.1038/ng2022 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Guangfu Jin
    • 1
  • Lingyi Lu
    • 1
  • Kathleen A. Cooney
    • 2
    • 3
  • Anna M. Ray
    • 2
    • 3
  • Kimberly A. Zuhlke
    • 2
    • 3
  • Ethan M. Lange
    • 2
    • 4
  • Lisa A. Cannon-Albright
    • 5
    • 6
  • Nicola J. Camp
    • 5
  • Craig C. Teerlink
    • 5
  • Liesel M. FitzGerald
    • 7
  • Janet L. Stanford
    • 7
  • Kathleen E. Wiley
    • 8
  • Sarah D. Isaacs
    • 8
  • Patrick C. Walsh
    • 8
  • William D. Foulkes
    • 9
  • Graham G. Giles
    • 10
    • 11
  • John L. Hopper
    • 11
  • Gianluca Severi
    • 10
    • 11
  • Ros Eeles
    • 12
  • Doug Easton
    • 13
  • Zsofia Kote-Jarai
    • 12
  • Michelle Guy
    • 12
  • Antje Rinckleb
    • 14
    • 15
  • Christiane Maier
    • 14
    • 15
  • Walther Vogel
    • 15
  • Geraldine Cancel-Tassin
    • 16
  • Christophe Egrot
    • 16
  • Olivier Cussenot
    • 16
  • Stephen N. Thibodeau
    • 17
  • Shannon K. McDonnell
    • 18
  • Daniel J. Schaid
    • 18
  • Fredrik Wiklund
    • 19
  • Henrik Grönberg
    • 19
  • Monica Emanuelsson
    • 20
  • Alice S. Whittemore
    • 21
  • Ingrid Oakley-Girvan
    • 22
    • 23
  • Chih-Lin Hsieh
    • 24
    • 25
  • Tiina Wahlfors
    • 26
    • 27
  • Teuvo Tammela
    • 28
  • Johanna Schleutker
    • 29
  • William J. Catalona
    • 30
  • S. Lilly Zheng
    • 1
  • Elaine A. Ostrander
    • 31
    Email author
  • William B. Isaacs
    • 8
    Email author
  • Jianfeng Xu
    • 1
    Email author
  • International Consortium for Prostate Cancer Genetics
  1. 1.Data Coordinating Center for the ICPCG and Center for Cancer GenomicsWake Forest University School of MedicineWinston-SalemUSA
  2. 2.University of Michigan ICPCG GroupAnn ArborUSA
  3. 3.Departments of Internal Medicine and Urology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborUSA
  4. 4.Departments of Genetics and BiostatisticsUniversity of North CarolinaChapel HillUSA
  5. 5.University of Utah ICPCG Group, Division of Genetic Epidemiology, Department of MedicineUniversity of Utah School of MedicineSalt Lake CityUSA
  6. 6.George E. Wahlen Department of Veterans Affairs Medical CenterSalt Lake CityUSA
  7. 7.Division of Public Health SciencesFred Hutchinson Cancer Research Center (FHCRC)SeattleUSA
  8. 8.Johns Hopkins University ICPCG Group, Department of UrologyJohns Hopkins Medical InstitutionsBaltimoreUSA
  9. 9.Program in Cancer GeneticsMcGill UniversityMontrealCanada
  10. 10.Cancer Epidemiology CentreCancer Council VictoriaCarltonAustralia
  11. 11.Centre for Molecular, Environmental, Genetic, and Analytic EpidemiologyThe University of MelbourneMelbourneAustralia
  12. 12.The Institute of Cancer ResearchSuttonUK
  13. 13.Departments of Public Health and Primary Care and OncologyUniversity of CambridgeCambridgeUK
  14. 14.Department of UrologyUniversity of UlmUlmGermany
  15. 15.Institute for Human GeneticsUniversity of UlmUlmGermany
  16. 16.CeRePP ICPCG Group, Hopital Tenon, Assistance Publique-Hopitaux de ParisParisFrance
  17. 17.Department of Lab Medicine and PathologyMayo ClinicRochesterUSA
  18. 18.Department of Health Sciences ResearchMayo ClinicRochesterUSA
  19. 19.Department of Medical Epidemiology and BiostatisticsKarolinska InstitutetStockholmSweden
  20. 20.Oncologic CentreUmeå UniversityUmeåSweden
  21. 21.Department of Health Research and PolicyStanford School of MedicineStanfordUSA
  22. 22.Cancer Prevention Institute of CaliforniaFremontUSA
  23. 23.Department of Health Research and Policy, Stanford Cancer InstituteStanford School of MedicineStanfordUSA
  24. 24.Department of UrologyUniversity of Southern CaliforniaLos AngelesUSA
  25. 25.Department of Biochemistry and Molecular BiologyUniversity of Southern CaliforniaLos AngelesUSA
  26. 26.Institute of Biomedical TechnologyUniversity of Tampere, BioMediTechTampereFinland
  27. 27.Centre for Laboratory Medicine, Tampere University HospitalTampereFinland
  28. 28.Department of UrologyUniversity of Tampere and Tampere University HospitalTampereFinland
  29. 29.Department of Medical Biochemistry and GeneticsUniversity of TurkuTurkuFinland
  30. 30.Northwestern University ICPCG GroupNorthwestern University Feinberg School of MedicineChicagoUSA
  31. 31.Cancer Genetics Branch, National Human Genome Research Institute (NHGRI)National Institutes of Health (NIH)BethesdaUSA

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