Abstract
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1 × 10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72 × 10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 × 10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1341-1353 |
| Number of pages | 13 |
| Journal | Carcinogenesis |
| Volume | 36 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2015 |
ASJC Scopus subject areas
- Cancer Research
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Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. / Lawrenson, Kate; Iversen, Edwin S.; Tyrer, Jonathan; Weber, Rachel Palmieri; Concannon, Patrick; Hazelett, Dennis J.; Li, Qiyuan; Marks, Jeffrey R.; Berchuck, Andrew; Lee, Janet M.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Plisiecka-Halasa, Joanna; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Gronwald, Jacek; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Jakubowska, Anna; Paul, James; Jensen, Allan; Karlan, Beth Y.; Kjaer, Susanne Kruger; Kelemen, Linda E.; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Cannioto, Rikki; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; Nevanlinna, Heli; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Noor Azmi, Mat Adenan; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Pearce, Celeste L.; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Phelan, Catherine M.; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Budzilowska, Agnieszka; Sellers, Thomas A.; Shu, Xiao Ou; Shvetsov, Yurii B.; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Timorek, Agnieszka; Tworoger, Shelley S.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Woo, Yin Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Coetzee, Gerhard A.; Freedman, Matthew L.; Monteiro, Alvaro N.A.; Moes-Sosnowska, Joanna; Kupryjanczyk, Jolanta; Pharoah, Paul D.; Gayther, Simon A.; Schildkraut, Joellen M.
In: Carcinogenesis, Vol. 36, No. 11, 01.11.2015, p. 1341-1353.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer
AU - Lawrenson, Kate
AU - Iversen, Edwin S.
AU - Tyrer, Jonathan
AU - Weber, Rachel Palmieri
AU - Concannon, Patrick
AU - Hazelett, Dennis J.
AU - Li, Qiyuan
AU - Marks, Jeffrey R.
AU - Berchuck, Andrew
AU - Lee, Janet M.
AU - Aben, Katja K.H.
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia
AU - Bandera, Elisa V.
AU - Bean, Yukie
AU - Beckmann, Matthias W.
AU - Bisogna, Maria
AU - Bjorge, Line
AU - Bogdanova, Natalia
AU - Brinton, Louise A.
AU - Brooks-Wilson, Angela
AU - Bruinsma, Fiona
AU - Butzow, Ralf
AU - Campbell, Ian G.
AU - Carty, Karen
AU - Chang-Claude, Jenny
AU - Chenevix-Trench, Georgia
AU - Chen, Ann
AU - Chen, Zhihua
AU - Cook, Linda S.
AU - Cramer, Daniel W.
AU - Cunningham, Julie M.
AU - Cybulski, Cezary
AU - Plisiecka-Halasa, Joanna
AU - Dennis, Joe
AU - Dicks, Ed
AU - Doherty, Jennifer A.
AU - Dörk, Thilo
AU - du Bois, Andreas
AU - Eccles, Diana
AU - Easton, Douglas T.
AU - Edwards, Robert P.
AU - Eilber, Ursula
AU - Ekici, Arif B.
AU - Fasching, Peter A.
AU - Fridley, Brooke L.
AU - Gao, Yu Tang
AU - Gentry-Maharaj, Aleksandra
AU - Giles, Graham G.
AU - Glasspool, Rosalind
AU - Goode, Ellen L.
AU - Goodman, Marc T.
AU - Gronwald, Jacek
AU - Harter, Philipp
AU - Hasmad, Hanis Nazihah
AU - Hein, Alexander
AU - Heitz, Florian
AU - Hildebrandt, Michelle A.T.
AU - Hillemanns, Peter
AU - Hogdall, Estrid
AU - Hogdall, Claus
AU - Hosono, Satoyo
AU - Jakubowska, Anna
AU - Paul, James
AU - Jensen, Allan
AU - Karlan, Beth Y.
AU - Kjaer, Susanne Kruger
AU - Kelemen, Linda E.
AU - Kellar, Melissa
AU - Kelley, Joseph L.
AU - Kiemeney, Lambertus A.
AU - Krakstad, Camilla
AU - Lambrechts, Diether
AU - Lambrechts, Sandrina
AU - Le, Nhu D.
AU - Lee, Alice W.
AU - Cannioto, Rikki
AU - Leminen, Arto
AU - Lester, Jenny
AU - Levine, Douglas A.
AU - Liang, Dong
AU - Lissowska, Jolanta
AU - Lu, Karen
AU - Lubinski, Jan
AU - Lundvall, Lene
AU - Massuger, Leon F.A.G.
AU - Matsuo, Keitaro
AU - McGuire, Valerie
AU - McLaughlin, John R.
AU - Nevanlinna, Heli
AU - McNeish, Iain
AU - Menon, Usha
AU - Modugno, Francesmary
AU - Moysich, Kirsten B.
AU - Narod, Steven A.
AU - Nedergaard, Lotte
AU - Ness, Roberta B.
AU - Noor Azmi, Mat Adenan
AU - Odunsi, Kunle
AU - Olson, Sara H.
AU - Orlow, Irene
AU - Orsulic, Sandra
AU - Pearce, Celeste L.
AU - Pejovic, Tanja
AU - Pelttari, Liisa M.
AU - Permuth-Wey, Jennifer
AU - Phelan, Catherine M.
AU - Pike, Malcolm C.
AU - Poole, Elizabeth M.
AU - Ramus, Susan J.
AU - Risch, Harvey A.
AU - Rosen, Barry
AU - Rossing, Mary Anne
AU - Rothstein, Joseph H.
AU - Rudolph, Anja
AU - Runnebaum, Ingo B.
AU - Rzepecka, Iwona K.
AU - Salvesen, Helga B.
AU - Budzilowska, Agnieszka
AU - Sellers, Thomas A.
AU - Shu, Xiao Ou
AU - Shvetsov, Yurii B.
AU - Siddiqui, Nadeem
AU - Sieh, Weiva
AU - Song, Honglin
AU - Southey, Melissa C.
AU - Sucheston, Lara
AU - Tangen, Ingvild L.
AU - Teo, Soo Hwang
AU - Terry, Kathryn L.
AU - Thompson, Pamela J.
AU - Timorek, Agnieszka
AU - Tworoger, Shelley S.
AU - Van Nieuwenhuysen, Els
AU - Vergote, Ignace
AU - Vierkant, Robert A.
AU - Wang-Gohrke, Shan
AU - Walsh, Christine
AU - Wentzensen, Nicolas
AU - Whittemore, Alice S.
AU - Wicklund, Kristine G.
AU - Wilkens, Lynne R.
AU - Woo, Yin Ling
AU - Wu, Xifeng
AU - Wu, Anna H.
AU - Yang, Hannah
AU - Zheng, Wei
AU - Ziogas, Argyrios
AU - Coetzee, Gerhard A.
AU - Freedman, Matthew L.
AU - Monteiro, Alvaro N.A.
AU - Moes-Sosnowska, Joanna
AU - Kupryjanczyk, Jolanta
AU - Pharoah, Paul D.
AU - Gayther, Simon A.
AU - Schildkraut, Joellen M.
N1 - Funding Information: The scientific development and funding for this project were supported by the following: the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative (U19-CA148112); the COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07); and Department of Defense Award (W81XWH-12-1-0561, W81XWH-07-0449). F.M. was supported by National Institutes of Health K07-CA080668; S.S.T. and E.M.P. were supported in part by Department of Defense Award W81XWH-12-1-0561. Funding of the constituent studies was provided by: California Cancer Research Program (00-01389V-20170, 2II0200); Cancer Prevention Institute of California; Department of Defense (DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-02802); Fred C. and Katherine B. Andersen Foundation; Lon V Smith Foundation grant LVS-39420; Mayo Foundation; Minnesota Ovarian Cancer Alliance; National Institutes of Health (K07-CA095666, K07-CA143047, K22-CA138563); National Center for Research Resources/General Clinical Research Center grant M01-RR000056, N01-CN025403, N01-CN55424, N01-PC67001, N01-PC67010, P01-CA17054, P30-CA14089, P30-CA15083, P30-CA072720, P50-CA105009, P50-CA136393, P50-CA159981, R01-CA058860, R01-CA074850, R01-CA080742, R01-CA092044, R01-CA112523, R01-CA122443, R01-CA126841, R01-CA16056, R01-CA54419, R01-CA58598, R01-CA61132, R01-CA76016, R01-CA83918, R01-CA87538, R01-CA95023, R01-CA063678, R01 CA114343, R03-CA113148, R03-CA115195, U01-CA69417, U01-CA71966),UM1-CA182910; Rutgers Cancer Institute of New Jersey; and the US Public Health Service (PSA-042205). Personal support: K.L is supported by a K99/R00 grant from the National Cancer Institute (Grant number 1K99CA184415-01). D.F.E. is a Principal Research Fellow of Cancer Research UK. G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council. B.K. holds an American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. Publisher Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1 × 10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72 × 10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 × 10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
AB - Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1 × 10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72 × 10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70 × 10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
UR - http://www.scopus.com/inward/record.url?scp=85016071187&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016071187&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgv138
DO - 10.1093/carcin/bgv138
M3 - Article
C2 - 26424751
AN - SCOPUS:85016071187
VL - 36
SP - 1341
EP - 1353
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 11
ER -