A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history

Rick A Kittles, A. B. Boffoe-Bonnie, T. Y. Moses, C. M. Robbins, C. Ahaghotu, P. Huusko, C. Pettaway, S. Vijayakumar, J. Bennett, G. Hoke, T. Mason, S. Weinrich, J. M. Trent, F. S. Collins, S. Mousses, J. Bailey-Wilson, P. Furbert-Harris, G. Dunston, I. J. Powell, J. D. Carpten

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)507-511
Number of pages5
JournalJournal of Medical Genetics
Volume43
Issue number6
DOIs
StatePublished - Jun 2006
Externally publishedYes

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Nonsense Codon
African Americans
Prostatic Neoplasms
Tumor Suppressor Genes
Mutation
Genes
Alleles
Odds Ratio
Confidence Intervals
Familial Prostate cancer

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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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. / Kittles, Rick A; Boffoe-Bonnie, A. B.; Moses, T. Y.; Robbins, C. M.; Ahaghotu, C.; Huusko, P.; Pettaway, C.; Vijayakumar, S.; Bennett, J.; Hoke, G.; Mason, T.; Weinrich, S.; Trent, J. M.; Collins, F. S.; Mousses, S.; Bailey-Wilson, J.; Furbert-Harris, P.; Dunston, G.; Powell, I. J.; Carpten, J. D.

In: Journal of Medical Genetics, Vol. 43, No. 6, 06.2006, p. 507-511.

Research output: Contribution to journalArticle

Kittles, RA, Boffoe-Bonnie, AB, Moses, TY, Robbins, CM, Ahaghotu, C, Huusko, P, Pettaway, C, Vijayakumar, S, Bennett, J, Hoke, G, Mason, T, Weinrich, S, Trent, JM, Collins, FS, Mousses, S, Bailey-Wilson, J, Furbert-Harris, P, Dunston, G, Powell, IJ & Carpten, JD 2006, 'A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history', Journal of Medical Genetics, vol. 43, no. 6, pp. 507-511. https://doi.org/10.1136/jmg.2005.035790
Kittles, Rick A ; Boffoe-Bonnie, A. B. ; Moses, T. Y. ; Robbins, C. M. ; Ahaghotu, C. ; Huusko, P. ; Pettaway, C. ; Vijayakumar, S. ; Bennett, J. ; Hoke, G. ; Mason, T. ; Weinrich, S. ; Trent, J. M. ; Collins, F. S. ; Mousses, S. ; Bailey-Wilson, J. ; Furbert-Harris, P. ; Dunston, G. ; Powell, I. J. ; Carpten, J. D. / A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history. In: Journal of Medical Genetics. 2006 ; Vol. 43, No. 6. pp. 507-511.
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title = "A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history",
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.",
author = "Kittles, {Rick A} and Boffoe-Bonnie, {A. B.} and Moses, {T. Y.} and Robbins, {C. M.} and C. Ahaghotu and P. Huusko and C. Pettaway and S. Vijayakumar and J. Bennett and G. Hoke and T. Mason and S. Weinrich and Trent, {J. M.} and Collins, {F. S.} and S. Mousses and J. Bailey-Wilson and P. Furbert-Harris and G. Dunston and Powell, {I. J.} and Carpten, {J. D.}",
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T1 - A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history

AU - Kittles, Rick A

AU - Boffoe-Bonnie, A. B.

AU - Moses, T. Y.

AU - Robbins, C. M.

AU - Ahaghotu, C.

AU - Huusko, P.

AU - Pettaway, C.

AU - Vijayakumar, S.

AU - Bennett, J.

AU - Hoke, G.

AU - Mason, T.

AU - Weinrich, S.

AU - Trent, J. M.

AU - Collins, F. S.

AU - Mousses, S.

AU - Bailey-Wilson, J.

AU - Furbert-Harris, P.

AU - Dunston, G.

AU - Powell, I. J.

AU - Carpten, J. D.

PY - 2006/6

Y1 - 2006/6

N2 - 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.

AB - 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.

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