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A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history
  1. R A Kittles1,
  2. A B Baffoe-Bonnie2,
  3. T Y Moses3,
  4. C M Robbins3,
  5. C Ahaghotu4,
  6. P Huusko2,
  7. C Pettaway5,
  8. S Vijayakumar6,
  9. J Bennett7,
  10. G Hoke8,
  11. T Mason9,
  12. S Weinrich10,
  13. J M Trent3,
  14. F S Collins11,
  15. S Mousses3,
  16. J Bailey-Wilson12,
  17. P Furbert-Harris4,
  18. G Dunston4,
  19. I J Powell13,
  20. J D Carpten3
  1. 1Department of Molecular Virology, Immunology and Medical Genetics, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Ohio State University, Columbus, OH, USA
  2. 2Population Science Division, Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
  3. 3Genetic Basis of Human Disease Research Division, Translational Genomics Research Institute, Phoenix, AZ, USA
  4. 4National Genome Center at Howard University, Washington, DC, USA
  5. 5Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  6. 6Department of Radiation Oncology, UC Davis Cancer Center, University of California, Davis, Sacramento, CA, USA
  7. 7Midtown Urology Surgical Center, Atlanta, GA, USA
  8. 8Department of Urology, Columbia University Medical Center, Columbia University, New York, NY, USA
  9. 9Department of Urology, University of Illinois at Chicago, Chicago, IL, USA
  10. 10Medical College of Georgia, School of Nursing, Augusta, GA, USA
  11. 11National Human Genome Research Institute, Bethesda, MD, USA
  12. 12Center for Inherited Disease Research, National Institutes of Health, Baltimore, MD, USA
  13. 13Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA
  1. Correspondence to:
 Dr R A Kittles
 Department of Molecular Virology, Immunology and Medical Genetics, Arthur G James Cancer Hospital and Richard J Solove Research Institute, The Ohio State University, 494 Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210, USA; pkittles.2{at}osu.edu

Abstract

Background: The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in ∼10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms.

Methods: Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case-control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification.

Results: Ten coding sequence variants were identified, including the K1019X (3055A→T) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055A→T mutation significantly increased risk for prostate cancer over twofold (Fisher’s two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association.

Conclusions: Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA.

  • AA, African American
  • AAHPC, African American Hereditary Prostate Cancer Study
  • AIM, ancestry informative marker
  • EA, European American
  • HPC, hereditary prostate cancer
  • PC, prostate cancer
  • PS, population stratification
  • PSA, prostate specific antigen
  • African Americans
  • EphB2 polymorphisms
  • admixture
  • hereditary prostate cancer
  • prostate cancer

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Footnotes

  • Published Online First 9 September 2005

  • Competing interests: there are no competing interests

  • The NCBI dbSNP website is available at www.ncbi.nlm.nih.gov/SNP.

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