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. DiCioccio; M. 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; 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

doi:10.1038/sj.bjc.6604820

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, 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 journal › Article › peer-review

45 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: OR_{homozygous(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, p_het 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 language	English (US)
Pages (from-to)	412-420
Number of pages	9
Journal	British journal of cancer
Volume	100
Issue number	2
DOIs	https://doi.org/10.1038/sj.bjc.6604820
State	Published - Jan 27 2009

Keywords

CYP3A4
Genetic susceptibility
Oestrogen metabolism
Ovarian cancer
Pooled-analyses

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1038/sj.bjc.6604820

Cite this

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

Pearce, CL, Near, AM, Van Den Berg, DJ, Ramus, SJ, Gentry-Maharaj, A, Menon, U, Gayther, SA, Anderson, AR, Edlund, CK, Wu, AH, Chen, X, Beesley, J, Webb, PM, Holt, SK, Chen, C, Doherty, JA, Rossing, MA, Whittemore, AS, McGuire, V, DiCioccio, RA, Goodman, MT, Lurie, G, Carney, ME, Wilkens, LR, Ness, RB, Moysich, KB, Edwards, R, Jennison, E, Kjaer, SK, Hogdall, E, Hogdall, CK, Goode, EL, Sellers, TA, Vierkant, RA, Cunningham, JC, Schildkraut, JM, Berchuck, A, Moorman, PG, Iversen, ES, Cramer, DW, Terry, KL, Vitonis, AF, Titus-Ernstoff, L, Song, H, Pharoah, PDP, Spurdle, AB, Anton-Culver, H, Ziogas, A, Brewster, W, Galitovskiy, V, Chenevix-Trench, G, Gertig, D, Vanden Bergh, T, Camaris, C, Crouch, R, Edwards, L, Hacker, N, Marsden, D, Robertson, G, DeFazio, A, Hung, J, Chiew, YE, Stenlake, A, Sullivan, H, Brand, A, Jaworski, R, Harnett, P, Wain, G, Green, A, Moore, S, Harrap, K, Sadkowsky, T, Purdie, D, Whiteman, D, Alexander, B, Ashover, P, Brown, S, Corrish, T, Green, L, Jackman, L, Martin, K, Ranieri, B, White, J, Mamers, P, Healy, D, Jobling, T, Maniolitas, T, McNealage, J, Rogers, P, Susil, B, Veitch, A, Constable, J, Ping Tong, S, Robinson, I, Simpson, I, Schmidt, T, Shirley, H, Viduka, S, Tran, H, Bilic, S, Glavinas, L, Zeps, N, Mellon, A, Robertson, R, Proietto, A, Braye, S, Otton, G, Bonaventura, T, Stewart, J, Friedlander, M, Maidens, J, Bell, D, Baron-Hay, S, Ferrier, A, Gard, G, Nevell, D, Young, B, Nattress, K, Beale, P, Beith, J, Carter, J, Dalrymple, C, Hamilton, A, Houghton, R, Russell, P, Crandon, A, Cummings, M, Horwood, K, Obermair, A, Wyld, D, Nicklin, J, Perrin, L, Ward, B, Papadimos, D, Davy, M, Hall, C, Dodd, T, Healy, T, Pittman, K, Henderson, D, Hyde, S, Miller, J, Pierdes, J, Jayde, V, Blomfield, P, Challis, D, McIntosh, R, Parker, A, Brown, B, Rome, R, Allen, D, Grant, P, Hyde, S, Laurie, R, Robbie, M, Traficante, N, Fereday, S, Bowes, L, Phillips, K, Rischin, D, Waring, P, Loughrey, M, O'Callaghan, N, Murray, B, Haviv, I, Billson, V, Galloway, S, Pyman, J, Quinn, M, Hammond, I, McCartney, A & Leung, Y 2009, 'Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium', British journal of cancer, vol. 100, no. 2, pp. 412-420. https://doi.org/10.1038/sj.bjc.6604820

@article{49c8cf9168c9419799bb7f9edc2cb16b,

title = "Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium",

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.",

keywords = "CYP3A4, Genetic susceptibility, Oestrogen metabolism, Ovarian cancer, Pooled-analyses",

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

note = "Funding Information: GEOCS: This work was funded by grants from the Roswell Park Alliance and National Institutes of Health Grants CA66190 and CA16056. Funding Information: SEARCH: This work was supported by Cancer Research-UK. We thank: Hannah Munday, Barbara Perkins, Mitul Shah, Clare Jordan, Judy West, Anabel Simpson, Sue Irvine, the search team: the local general practices and nurses and the East Anglian Cancer Registry for recruitment of the UK cases and the EPIC-Norfolk investigators for recruitment of the UK controls; PDPP is CRUK Senior Clinical Research Fellow. Funding Information: MAYO: This work was funded by National Institutes of Health Grants R01-CA86888 and R01-CA122443. Funding Information: Murray (PMCC); V Billson, S Galloway, J Pyman, M Quinn (Royal Women{\textquoteright}s Hospital); WA – I Hammond, A McCartney, Y Leung (King Edward Memorial Hospital, St John of God). Scientific Collaborators: I Haviv (PMCC); D Purdie, D Whiteman (QIMR); N Zeps (WARTN). GCT, ABS and PW are supported by the NHMRC. Additional support was provided by: US Army Medical Research and Materiel Command under DAMD17-01-1-0729, the Cancer Council Tasmania and Cancer Foundation of Western Australia (AOCS study); The National Health and Medical Research Council of Australia (199600) (ACS study). Funding Information: Hawaii: US Public Health Service grant R01-CA-58598, and contracts N01-CN-55424 and N01-PC-35137 from the National Cancer Institute, NIH, Department of Health and Human Services. Funding Information: NECC: This work was funded by National Institutes of Health Grants 5P50CA105009 and 5RO1CA054419. Funding Information: UCI: This research was supported by the National Institutes of Health Grants CA-58860, CA-92044 and the Lon V Smith Foundation Grant LVS-39420. Funding Information: We express our profound thanks to all the study participants who contributed to this research. Genotyping and the Ovarian Cancer Association Consortium are funded by the Ovarian Cancer Research Fund thanks to generous donations from the family and friends of Kathryn Sladek Smith. Funding Information: NCOCS: This work was funded by National Institutes of Health Grant 2-R01-CA76016. Funding Information: HOPE: This work was funded by National Institutes of Health Grant R01CA095023 and DAMD 17-02-1-0669.",

year = "2009",

month = jan,

day = "27",

doi = "10.1038/sj.bjc.6604820",

language = "English (US)",

volume = "100",

pages = "412--420",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium

AU - Pearce, C. L.

AU - Near, A. M.

AU - Van Den Berg, D. J.

AU - Ramus, S. J.

AU - Gentry-Maharaj, A.

AU - Menon, U.

AU - Gayther, S. A.

AU - Anderson, A. R.

AU - Edlund, C. K.

AU - Wu, A. H.

AU - Chen, X.

AU - Beesley, J.

AU - Webb, P. M.

AU - Holt, S. K.

AU - Chen, C.

AU - Doherty, J. A.

AU - Rossing, M. A.

AU - Whittemore, A. S.

AU - McGuire, V.

AU - DiCioccio, R. A.

AU - Goodman, M. T.

AU - Lurie, G.

AU - Carney, M. E.

AU - Wilkens, L. R.

AU - Ness, R. B.

AU - Moysich, K. B.

AU - Edwards, R.

AU - Jennison, E.

AU - Kjaer, S. K.

AU - Hogdall, E.

AU - Hogdall, C. K.

AU - Goode, E. L.

AU - Sellers, T. A.

AU - Vierkant, R. A.

AU - Cunningham, J. C.

AU - Schildkraut, J. M.

AU - Berchuck, A.

AU - Moorman, P. G.

AU - Iversen, E. S.

AU - Cramer, D. W.

AU - Terry, K. L.

AU - Vitonis, A. F.

AU - Titus-Ernstoff, L.

AU - Song, H.

AU - Pharoah, P. D.P.

AU - Spurdle, A. B.

AU - Anton-Culver, H.

AU - Ziogas, A.

AU - Brewster, W.

AU - Galitovskiy, V.

AU - Chenevix-Trench, G.

AU - Gertig, D.

AU - Vanden Bergh, T.

AU - Camaris, C.

AU - Crouch, R.

AU - Edwards, L.

AU - Hacker, N.

AU - Marsden, D.

AU - Robertson, G.

AU - DeFazio, A.

AU - Hung, J.

AU - Chiew, Y. E.

AU - Stenlake, A.

AU - Sullivan, H.

AU - Brand, A.

AU - Jaworski, R.

AU - Harnett, P.

AU - Wain, G.

AU - Green, A.

AU - Moore, S.

AU - Harrap, K.

AU - Sadkowsky, T.

AU - Purdie, D.

AU - Whiteman, D.

AU - Alexander, B.

AU - Ashover, P.

AU - Brown, S.

AU - Corrish, T.

AU - Green, L.

AU - Jackman, L.

AU - Martin, K.

AU - Ranieri, B.

AU - White, J.

AU - Mamers, P.

AU - Healy, D.

AU - Jobling, T.

AU - Maniolitas, T.

AU - McNealage, J.

AU - Rogers, P.

AU - Susil, B.

AU - Veitch, A.

AU - Constable, J.

AU - Ping Tong, S.

AU - Robinson, I.

AU - Simpson, I.

AU - Schmidt, T.

AU - Shirley, H.

AU - Viduka, S.

AU - Tran, H.

AU - Bilic, S.

AU - Glavinas, L.

AU - Zeps, N.

AU - Mellon, A.

AU - Robertson, R.

AU - Proietto, A.

AU - Braye, S.

AU - Otton, G.

AU - Bonaventura, T.

AU - Stewart, J.

AU - Friedlander, M.

AU - Maidens, J.

AU - Bell, D.

AU - Baron-Hay, S.

AU - Ferrier, A.

AU - Gard, G.

AU - Nevell, D.

AU - Young, B.

AU - Nattress, K.

AU - Beale, P.

AU - Beith, J.

AU - Carter, J.

AU - Dalrymple, C.

AU - Hamilton, A.

AU - Houghton, R.

AU - Russell, P.

AU - Crandon, A.

AU - Cummings, M.

AU - Horwood, K.

AU - Obermair, A.

AU - Wyld, D.

AU - Nicklin, J.

AU - Perrin, L.

AU - Ward, B.

AU - Papadimos, D.

AU - Davy, M.

AU - Hall, C.

AU - Dodd, T.

AU - Healy, T.

AU - Pittman, K.

AU - Henderson, D.

AU - Hyde, S.

AU - Miller, J.

AU - Pierdes, J.

AU - Jayde, V.

AU - Blomfield, P.

AU - Challis, D.

AU - McIntosh, R.

AU - Parker, A.

AU - Brown, B.

AU - Rome, R.

AU - Allen, D.

AU - Grant, P.

AU - Hyde, S.

AU - Laurie, R.

AU - Robbie, M.

AU - Traficante, N.

AU - Fereday, S.

AU - Bowes, L.

AU - Phillips, K.

AU - Rischin, D.

AU - Waring, P.

AU - Loughrey, M.

AU - O'Callaghan, N.

AU - Murray, B.

AU - Haviv, I.

AU - Billson, V.

AU - Galloway, S.

AU - Pyman, J.

AU - Quinn, M.

AU - Hammond, I.

AU - McCartney, A.

AU - Leung, Y.

N1 - Funding Information: GEOCS: This work was funded by grants from the Roswell Park Alliance and National Institutes of Health Grants CA66190 and CA16056. Funding Information: SEARCH: This work was supported by Cancer Research-UK. We thank: Hannah Munday, Barbara Perkins, Mitul Shah, Clare Jordan, Judy West, Anabel Simpson, Sue Irvine, the search team: the local general practices and nurses and the East Anglian Cancer Registry for recruitment of the UK cases and the EPIC-Norfolk investigators for recruitment of the UK controls; PDPP is CRUK Senior Clinical Research Fellow. Funding Information: MAYO: This work was funded by National Institutes of Health Grants R01-CA86888 and R01-CA122443. Funding Information: Murray (PMCC); V Billson, S Galloway, J Pyman, M Quinn (Royal Women’s Hospital); WA – I Hammond, A McCartney, Y Leung (King Edward Memorial Hospital, St John of God). Scientific Collaborators: I Haviv (PMCC); D Purdie, D Whiteman (QIMR); N Zeps (WARTN). GCT, ABS and PW are supported by the NHMRC. Additional support was provided by: US Army Medical Research and Materiel Command under DAMD17-01-1-0729, the Cancer Council Tasmania and Cancer Foundation of Western Australia (AOCS study); The National Health and Medical Research Council of Australia (199600) (ACS study). Funding Information: Hawaii: US Public Health Service grant R01-CA-58598, and contracts N01-CN-55424 and N01-PC-35137 from the National Cancer Institute, NIH, Department of Health and Human Services. Funding Information: NECC: This work was funded by National Institutes of Health Grants 5P50CA105009 and 5RO1CA054419. Funding Information: UCI: This research was supported by the National Institutes of Health Grants CA-58860, CA-92044 and the Lon V Smith Foundation Grant LVS-39420. Funding Information: We express our profound thanks to all the study participants who contributed to this research. Genotyping and the Ovarian Cancer Association Consortium are funded by the Ovarian Cancer Research Fund thanks to generous donations from the family and friends of Kathryn Sladek Smith. Funding Information: NCOCS: This work was funded by National Institutes of Health Grant 2-R01-CA76016. Funding Information: HOPE: This work was funded by National Institutes of Health Grant R01CA095023 and DAMD 17-02-1-0669.

PY - 2009/1/27

Y1 - 2009/1/27

N2 - 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.

AB - 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.

KW - CYP3A4

KW - Genetic susceptibility

KW - Oestrogen metabolism

KW - Ovarian cancer

KW - Pooled-analyses

UR - http://www.scopus.com/inward/record.url?scp=58749117371&partnerID=8YFLogxK

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U2 - 10.1038/sj.bjc.6604820

DO - 10.1038/sj.bjc.6604820

M3 - Article

C2 - 19127255

AN - SCOPUS:58749117371

SN - 0007-0920

VL - 100

SP - 412

EP - 420

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 2

ER -

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

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