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

Chenevix-Trench, Georgia (2009) Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. Nature Publishing Group, 100 2: 412-420. doi:10.1038/sj.bjc.6604820


Author Chenevix-Trench, Georgia
Title Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium
Formatted title
Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium
Journal name Nature Publishing Group   Check publisher's open access policy
ISSN 0007-0920
1532-1827
Publication date 2009-01-01
Year available 2009
Sub-type Article (original research)
DOI 10.1038/sj.bjc.6604820
Open Access Status DOI
Volume 100
Issue 2
Start page 412
End page 420
Total pages 9
Editor Adrian Harris
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2010
Language eng
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 P0.10 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. C L Pearce1, A M Near2, D J Van Den Berg3, S J Ramus4, A Gentry-Maharaj5, U Menon5, S A Gayther4, A R Anderson1, C K Edlund3, A H Wu1, X Chen6, J Beesley6, P M Webb6, S K Holt7, C Chen7, J A Doherty7, M A Rossing7, A S Whittemore8, V McGuire8, R A DiCioccio9, M T Goodman10, G Lurie10, M E Carney10, L R Wilkens10, R B Ness11, K B Moysich12, R Edwards13, E Jennison14, S K Kjaer15, E Hogdall15, C K Hogdall16, E L Goode17, T A Sellers18, R A Vierkant17, J C Cunningham17, J M Schildkraut19, A Berchuck20, P G Moorman19, E S Iversen21, D W Cramer22, K L Terry22, A F Vitonis22, L Titus-Ernstoff23, H Song24, P D P Pharoah24, A B Spurdle6, H Anton-Culver25, A Ziogas25, W Brewster26, V Galitovskiy25, G Chenevix-Trench6, Australian Cancer Study (Ovarian Cancer)6 and Australian Ovarian Cancer Study Group6,27 on behalf of the Ovarian Cancer Association Consortium
Formatted 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 P0.10 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.

C L Pearce1, A M Near2, D J Van Den Berg3, S J Ramus4, A Gentry-Maharaj5, U Menon5, S A Gayther4, A R Anderson1, C K Edlund3, A H Wu1, X Chen6, J Beesley6, P M Webb6, S K Holt7, C Chen7, J A Doherty7, M A Rossing7, A S Whittemore8, V McGuire8, R A DiCioccio9, M T Goodman10, G Lurie10, M E Carney10, L R Wilkens10, R B Ness11, K B Moysich12, R Edwards13, E Jennison14, S K Kjaer15, E Hogdall15, C K Hogdall16, E L Goode17, T A Sellers18, R A Vierkant17, J C Cunningham17, J M Schildkraut19, A Berchuck20, P G Moorman19, E S Iversen21, D W Cramer22, K L Terry22, A F Vitonis22, L Titus-Ernstoff23, H Song24, P D P Pharoah24, A B Spurdle6, H Anton-Culver25, A Ziogas25, W Brewster26, V Galitovskiy25, G Chenevix-Trench6, Australian Cancer Study (Ovarian Cancer)6 and Australian Ovarian Cancer Study Group6,27 on behalf of the Ovarian Cancer Association Consortium



Keyword Ovarian cancer
Pooled-analyses
CYP3A4
Oestrogen metabolism
Genetic susceptibility
Q-Index Code C1
Q-Index Status Provisional Code
Additional Notes complete author list entered after abstract

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Thu, 01 Apr 2010, 01:30:12 EST by Amanda Jones on behalf of Medicine - Royal Brisbane and Women's Hospital