Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer

Simon A. Gayther, Honglin Song, Susan J. Ramus, Susan Krüger Kjaer, Alice S. Whittemore, Lydia Quaye, Jonathan Tyrer, Danielle Shadforth, Estrid Hogdall, Claus Hogdall, Jan Blaeker, Richard DiCioccio, Valerie McGuire, Penelope M. Webb, Jonathan Beesley, Adele C. Green, David C. Whiteman, Marc T. Goodman, Galina Lurie, Michael E. CarneyFrancesmary Modugno, Roberta B. Ness, Robert P. Edwards, Kirsten B. Moysich, Ellen L Goode, Fergus J Couch, Julie M Cunningham, Thomas A. Sellers, Anna H. Wu, Malcolm C. Pike, Edwin S. Iversen, Jeffrey R. Marks, Montserrat Garcia-Closas, Louise Brinton, Jolanta Lissowska, Beata Peplonska, Douglas F. Easton, Ian Jacobs, Bruce A J Ponder, Joellen Schildkraut, C. Leigh Pearce, Georgia Chenevix-Trench, Andrew Berchuck, Paul D P Pharoah

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control - CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D - and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

Original languageEnglish (US)
Pages (from-to)3027-3035
Number of pages9
JournalCancer Research
Volume67
Issue number7
DOIs
StatePublished - Apr 1 2007

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cdc Genes
Cell Cycle Checkpoints
Single Nucleotide Polymorphism
Ovarian Neoplasms
Genes
p16 Genes
Neoplasm Genes
Genetic Association Studies
Poland
Denmark
Ovarian epithelial cancer
Case-Control Studies
Logistic Models
Alleles
Genotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gayther, S. A., Song, H., Ramus, S. J., Kjaer, S. K., Whittemore, A. S., Quaye, L., ... Pharoah, P. D. P. (2007). Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. Cancer Research, 67(7), 3027-3035. https://doi.org/10.1158/0008-5472.CAN-06-3261

Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. / Gayther, Simon A.; Song, Honglin; Ramus, Susan J.; Kjaer, Susan Krüger; Whittemore, Alice S.; Quaye, Lydia; Tyrer, Jonathan; Shadforth, Danielle; Hogdall, Estrid; Hogdall, Claus; Blaeker, Jan; DiCioccio, Richard; McGuire, Valerie; Webb, Penelope M.; Beesley, Jonathan; Green, Adele C.; Whiteman, David C.; Goodman, Marc T.; Lurie, Galina; Carney, Michael E.; Modugno, Francesmary; Ness, Roberta B.; Edwards, Robert P.; Moysich, Kirsten B.; Goode, Ellen L; Couch, Fergus J; Cunningham, Julie M; Sellers, Thomas A.; Wu, Anna H.; Pike, Malcolm C.; Iversen, Edwin S.; Marks, Jeffrey R.; Garcia-Closas, Montserrat; Brinton, Louise; Lissowska, Jolanta; Peplonska, Beata; Easton, Douglas F.; Jacobs, Ian; Ponder, Bruce A J; Schildkraut, Joellen; Pearce, C. Leigh; Chenevix-Trench, Georgia; Berchuck, Andrew; Pharoah, Paul D P.

In: Cancer Research, Vol. 67, No. 7, 01.04.2007, p. 3027-3035.

Research output: Contribution to journalArticle

Gayther, SA, Song, H, Ramus, SJ, Kjaer, SK, Whittemore, AS, Quaye, L, Tyrer, J, Shadforth, D, Hogdall, E, Hogdall, C, Blaeker, J, DiCioccio, R, McGuire, V, Webb, PM, Beesley, J, Green, AC, Whiteman, DC, Goodman, MT, Lurie, G, Carney, ME, Modugno, F, Ness, RB, Edwards, RP, Moysich, KB, Goode, EL, Couch, FJ, Cunningham, JM, Sellers, TA, Wu, AH, Pike, MC, Iversen, ES, Marks, JR, Garcia-Closas, M, Brinton, L, Lissowska, J, Peplonska, B, Easton, DF, Jacobs, I, Ponder, BAJ, Schildkraut, J, Pearce, CL, Chenevix-Trench, G, Berchuck, A & Pharoah, PDP 2007, 'Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer', Cancer Research, vol. 67, no. 7, pp. 3027-3035. https://doi.org/10.1158/0008-5472.CAN-06-3261
Gayther, Simon A. ; Song, Honglin ; Ramus, Susan J. ; Kjaer, Susan Krüger ; Whittemore, Alice S. ; Quaye, Lydia ; Tyrer, Jonathan ; Shadforth, Danielle ; Hogdall, Estrid ; Hogdall, Claus ; Blaeker, Jan ; DiCioccio, Richard ; McGuire, Valerie ; Webb, Penelope M. ; Beesley, Jonathan ; Green, Adele C. ; Whiteman, David C. ; Goodman, Marc T. ; Lurie, Galina ; Carney, Michael E. ; Modugno, Francesmary ; Ness, Roberta B. ; Edwards, Robert P. ; Moysich, Kirsten B. ; Goode, Ellen L ; Couch, Fergus J ; Cunningham, Julie M ; Sellers, Thomas A. ; Wu, Anna H. ; Pike, Malcolm C. ; Iversen, Edwin S. ; Marks, Jeffrey R. ; Garcia-Closas, Montserrat ; Brinton, Louise ; Lissowska, Jolanta ; Peplonska, Beata ; Easton, Douglas F. ; Jacobs, Ian ; Ponder, Bruce A J ; Schildkraut, Joellen ; Pearce, C. Leigh ; Chenevix-Trench, Georgia ; Berchuck, Andrew ; Pharoah, Paul D P. / Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer. In: Cancer Research. 2007 ; Vol. 67, No. 7. pp. 3027-3035.
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abstract = "High-risk susceptibility genes explain <40{\%} of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control - CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D - and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.",
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T1 - Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer

AU - Gayther, Simon A.

AU - Song, Honglin

AU - Ramus, Susan J.

AU - Kjaer, Susan Krüger

AU - Whittemore, Alice S.

AU - Quaye, Lydia

AU - Tyrer, Jonathan

AU - Shadforth, Danielle

AU - Hogdall, Estrid

AU - Hogdall, Claus

AU - Blaeker, Jan

AU - DiCioccio, Richard

AU - McGuire, Valerie

AU - Webb, Penelope M.

AU - Beesley, Jonathan

AU - Green, Adele C.

AU - Whiteman, David C.

AU - Goodman, Marc T.

AU - Lurie, Galina

AU - Carney, Michael E.

AU - Modugno, Francesmary

AU - Ness, Roberta B.

AU - Edwards, Robert P.

AU - Moysich, Kirsten B.

AU - Goode, Ellen L

AU - Couch, Fergus J

AU - Cunningham, Julie M

AU - Sellers, Thomas A.

AU - Wu, Anna H.

AU - Pike, Malcolm C.

AU - Iversen, Edwin S.

AU - Marks, Jeffrey R.

AU - Garcia-Closas, Montserrat

AU - Brinton, Louise

AU - Lissowska, Jolanta

AU - Peplonska, Beata

AU - Easton, Douglas F.

AU - Jacobs, Ian

AU - Ponder, Bruce A J

AU - Schildkraut, Joellen

AU - Pearce, C. Leigh

AU - Chenevix-Trench, Georgia

AU - Berchuck, Andrew

AU - Pharoah, Paul D P

PY - 2007/4/1

Y1 - 2007/4/1

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AB - High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)-tagging approach to evaluate common variants in 13 genes involved in cell cycle control - CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D - and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (∼1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (∼2,000 cases and ∼3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85-0.98) for rs3731257; and OR, 0.93 (0.87-0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies.

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