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 language | English (US) |
|---|---|
| Pages (from-to) | 412-420 |
| Number of pages | 9 |
| Journal | British journal of cancer |
| Volume | 100 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 27 2009 |
Keywords
- CYP3A4
- Genetic susceptibility
- Oestrogen metabolism
- Ovarian cancer
- Pooled-analyses
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. / 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.; DiCioccio, R. A.; Goodman, M. T.; Lurie, G.; Carney, M. E.; Wilkens, L. R.; Ness, R. B.; Moysich, K. B.; Edwards, R.; Jennison, E.; Kjaer, S. K.; Hogdall, E.; Hogdall, C. K.; Goode, E. L.; Sellers, T. A.; Vierkant, R. A.; Cunningham, J. C.; Schildkraut, J. M.; Berchuck, A.; Moorman, P. G.; Iversen, E. S.; Cramer, D. W.; Terry, K. L.; Vitonis, A. F.; Titus-Ernstoff, L.; Song, H.; Pharoah, P. D.P.; Spurdle, A. B.; 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, Y. E.; 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.
In: British journal of cancer, Vol. 100, No. 2, 27.01.2009, p. 412-420.Research output: Contribution to journal › Article › peer-review
}
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: 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: 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: GEOCS: This work was funded by grants from the Roswell Park Alliance and National Institutes of Health Grants CA66190 and CA16056. 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: HOPE: This work was funded by National Institutes of Health Grant R01CA095023 and DAMD 17-02-1-0669. Funding Information: MAYO: This work was funded by National Institutes of Health Grants R01-CA86888 and R01-CA122443. Funding Information: NECC: This work was funded by National Institutes of Health Grants 5P50CA105009 and 5RO1CA054419. Funding Information: NCOCS: This work was funded by National Institutes of Health Grant 2-R01-CA76016. 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: 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: USC: This work was funded by the California Cancer Research Program Grants 00-01389V-20170 and 2110200, US Public Health Service Grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148, and California Department of Health Services subcontract 050-E8709 as part of its statewide cancer reporting programme.
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
UR - http://www.scopus.com/inward/citedby.url?scp=58749117371&partnerID=8YFLogxK
U2 - 10.1038/sj.bjc.6604820
DO - 10.1038/sj.bjc.6604820
M3 - Article
C2 - 19127255
AN - SCOPUS:58749117371
VL - 100
SP - 412
EP - 420
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 2
ER -