Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

C. L. Pearce, A. M. Near, D. J. Van Den Berg, S. J. Ramus, A. Gentry-Maharaj, U. Menon, S. A. Gayther, A. R. Anderson, C. K. Edlund, A. H. Wu, X. Chen, J. Beesley, P. M. Webb, S. K. Holt, C. Chen, J. A. Doherty, M. A. Rossing, A. S. Whittemore, V. McGuire, R. A. DiCioccioM. T. Goodman, G. Lurie, M. E. Carney, L. R. Wilkens, R. B. Ness, K. B. Moysich, R. Edwards, E. Jennison, S. K. Kjaer, E. Hogdall, C. K. Hogdall, E. L. Goode, T. A. Sellers, R. A. Vierkant, J. C. Cunningham, J. M. Schildkraut, A. Berchuck, P. G. Moorman, E. S. Iversen, D. W. Cramer, K. L. Terry, A. F. Vitonis, L. Titus-Ernstoff, H. Song, P. D.P. Pharoah, A. B. Spurdle, H. Anton-Culver, A. Ziogas, W. Brewster, V. Galitovskiy, G. Chenevix-Trench, D. Gertig, T. Vanden Bergh, C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, A. DeFazio, J. Hung, Y. E. Chiew, A. Stenlake, H. Sullivan, A. Brand, R. Jaworski, P. Harnett, G. Wain, A. Green, P. Webb, S. Moore, K. Harrap, T. Sadkowsky, D. Purdie, D. Whiteman, B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Martin, B. Ranieri, J. White, P. Mamers, D. Healy, T. Jobling, T. Maniolitas, J. McNealage, P. Rogers, B. Susil, A. Veitch, J. Constable, S. Ping Tong, I. Robinson, I. Simpson, T. Schmidt, H. Shirley, S. Viduka, H. Tran, S. Bilic, L. Glavinas, N. Zeps, A. Mellon, R. Robertson, A. Proietto, S. Braye, G. Otton, T. Bonaventura, J. Stewart, M. Friedlander, J. Maidens, D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, B. Young, K. Nattress, P. Beale, J. Beith, J. Carter, C. Dalrymple, A. Hamilton, R. Houghton, P. Russell, A. Crandon, M. Cummings, K. Horwood, A. Obermair, D. Wyld, J. Nicklin, L. Perrin, B. Ward, D. Papadimos, M. Davy, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, S. Hyde, J. Miller, J. Pierdes, V. Jayde, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, N. Traficante, S. Fereday, L. Bowes, K. Phillips, D. Rischin, P. Waring, M. Loughrey, N. O'Callaghan, B. Murray, I. Haviv, V. Billson, S. Galloway, J. Pyman, M. Quinn, I. Hammond, A. McCartney, Y. Leung

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P≤0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: ORhomozygous(hom)=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, phet across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Original languageEnglish (US)
Pages (from-to)412-420
Number of pages9
JournalBritish journal of cancer
Volume100
Issue number2
DOIs
StatePublished - Jan 27 2009

Keywords

  • CYP3A4
  • Genetic susceptibility
  • Oestrogen metabolism
  • Ovarian cancer
  • Pooled-analyses

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Pearce, C. L., Near, A. M., Van Den Berg, D. J., Ramus, S. J., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Anderson, A. R., Edlund, C. K., Wu, A. H., Chen, X., Beesley, J., Webb, P. M., Holt, S. K., Chen, C., Doherty, J. A., Rossing, M. A., Whittemore, A. S., McGuire, V., ... Leung, Y. (2009). Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. British journal of cancer, 100(2), 412-420. https://doi.org/10.1038/sj.bjc.6604820