Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Kate Lawrenson; Edwin S. Iversen; Jonathan Tyrer; Rachel Palmieri Weber; Patrick Concannon; Dennis J. Hazelett; Qiyuan Li; Jeffrey R. Marks; Andrew Berchuck; Janet M. Lee; Katja K.H. Aben; Hoda Anton-Culver; Natalia Antonenkova; Elisa V. Bandera; Yukie Bean; Matthias W. Beckmann; Maria Bisogna; Line Bjorge; Natalia Bogdanova; Louise A. Brinton; Angela Brooks-Wilson; Fiona Bruinsma; Ralf Butzow; Ian G. Campbell; Karen Carty; Jenny Chang-Claude; Georgia Chenevix-Trench; Ann Chen; Zhihua Chen; Linda S. Cook; Daniel W. Cramer; Julie M. Cunningham; Cezary Cybulski; Joanna Plisiecka-Halasa; Joe Dennis; Ed Dicks; Jennifer A. Doherty; Thilo Dörk; Andreas du Bois; Diana Eccles; Douglas T. Easton; Robert P. Edwards; Ursula Eilber; Arif B. Ekici; Peter A. Fasching; Brooke L. Fridley; Yu Tang Gao; Aleksandra Gentry-Maharaj; Graham G. Giles; Rosalind Glasspool; Ellen L. Goode; Marc T. Goodman; Jacek Gronwald; Philipp Harter; Hanis Nazihah Hasmad; Alexander Hein; Florian Heitz; Michelle A.T. Hildebrandt; Peter Hillemanns; Estrid Hogdall; Claus Hogdall; Satoyo Hosono; Anna Jakubowska; James Paul; Allan Jensen; Beth Y. Karlan; Susanne Kruger Kjaer; Linda E. Kelemen; Melissa Kellar; Joseph L. Kelley; Lambertus A. Kiemeney; Camilla Krakstad; Diether Lambrechts; Sandrina Lambrechts; Nhu D. Le; Alice W. Lee; Rikki Cannioto; Arto Leminen; Jenny Lester; Douglas A. Levine; Dong Liang; Jolanta Lissowska; Karen Lu; Jan Lubinski; Lene Lundvall; Leon F.A.G. Massuger; Keitaro Matsuo; Valerie McGuire; John R. McLaughlin; Heli Nevanlinna; Iain McNeish; Usha Menon; Francesmary Modugno; Kirsten B. Moysich; Steven A. Narod; Lotte Nedergaard; Roberta B. Ness; Mat Adenan Noor Azmi; Kunle Odunsi; Sara H. Olson; Irene Orlow; Sandra Orsulic; Celeste L. Pearce; Tanja Pejovic; Liisa M. Pelttari; Jennifer Permuth-Wey; Catherine M. Phelan; Malcolm C. Pike; Elizabeth M. Poole; Susan J. Ramus; Harvey A. Risch; Barry Rosen; Mary Anne Rossing; Joseph H. Rothstein; Anja Rudolph; Ingo B. Runnebaum; Iwona K. Rzepecka; Helga B. Salvesen; Agnieszka Budzilowska; Thomas A. Sellers; Xiao Ou Shu; Yurii B. Shvetsov; Nadeem Siddiqui; Weiva Sieh; Honglin Song; Melissa C. Southey; Lara Sucheston; Ingvild L. Tangen; Soo Hwang Teo; Kathryn L. Terry; Pamela J. Thompson; Agnieszka Timorek; Shelley S. Tworoger; Els Van Nieuwenhuysen; Ignace Vergote; Robert A. Vierkant; Shan Wang-Gohrke; Christine Walsh; Nicolas Wentzensen; Alice S. Whittemore; Kristine G. Wicklund; Lynne R. Wilkens; Yin Ling Woo; Xifeng Wu; Anna H. Wu; Hannah Yang; Wei Zheng; Argyrios Ziogas; Gerhard A. Coetzee; Matthew L. Freedman; Alvaro N.A. Monteiro; Joanna Moes-Sosnowska; Jolanta Kupryjanczyk; Paul D. Pharoah; Simon A. Gayther; Joellen M. Schildkraut

doi:10.1093/carcin/bgv138

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

Kate Lawrenson, Edwin S. Iversen, Jonathan Tyrer, Rachel Palmieri Weber, Patrick Concannon, Dennis J. Hazelett, Qiyuan Li, Jeffrey R. Marks, Andrew Berchuck, Janet M. Lee, Katja K.H. Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V. Bandera, Yukie Bean, Matthias W. Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A. BrintonAngela Brooks-Wilson, Fiona Bruinsma, Ralf Butzow, Ian G. Campbell, Karen Carty, Jenny Chang-Claude, Georgia Chenevix-Trench, Ann Chen, Zhihua Chen, Linda S. Cook, Daniel W. Cramer, Julie M. Cunningham, Cezary Cybulski, Joanna Plisiecka-Halasa, Joe Dennis, Ed Dicks, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Diana Eccles, Douglas T. Easton, Robert P. Edwards, Ursula Eilber, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Yu Tang Gao, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind Glasspool, Ellen L. Goode, Marc T. Goodman, Jacek Gronwald, Philipp Harter, Hanis Nazihah Hasmad, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus Hogdall, Satoyo Hosono, Anna Jakubowska, James Paul, Allan Jensen, Beth Y. Karlan, Susanne Kruger Kjaer, Linda E. Kelemen, Melissa Kellar, Joseph L. Kelley, Lambertus A. Kiemeney, Camilla Krakstad, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Alice W. Lee, Rikki Cannioto, Arto Leminen, Jenny Lester, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F.A.G. Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Heli Nevanlinna, Iain McNeish, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Mat Adenan Noor Azmi, Kunle Odunsi, Sara H. Olson, Irene Orlow, Sandra Orsulic, Celeste L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Jennifer Permuth-Wey, Catherine M. Phelan, Malcolm C. Pike, Elizabeth M. Poole, Susan J. Ramus, Harvey A. Risch, Barry Rosen, Mary Anne Rossing, Joseph H. Rothstein, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Agnieszka Budzilowska, Thomas A. Sellers, Xiao Ou Shu, Yurii B. Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C. Southey, Lara Sucheston, Ingvild L. Tangen, Soo Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Agnieszka Timorek, Shelley S. Tworoger, Els Van Nieuwenhuysen, Ignace Vergote, Robert A. Vierkant, Shan Wang-Gohrke, Christine Walsh, Nicolas Wentzensen, Alice S. Whittemore, Kristine G. Wicklund, Lynne R. Wilkens, Yin Ling Woo, Xifeng Wu, Anna H. Wu, Hannah Yang, Wei Zheng, Argyrios Ziogas, Gerhard A. Coetzee, Matthew L. Freedman, Alvaro N.A. Monteiro, Joanna Moes-Sosnowska, Jolanta Kupryjanczyk, Paul D. Pharoah, Simon A. Gayther, Joellen M. Schildkraut

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

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	https://doi.org/10.1093/carcin/bgv138
State	Published - Nov 1 2015

ASJC Scopus subject areas

Cancer Research

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10.1093/carcin/bgv138

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Lawrenson, K., Iversen, E. S., Tyrer, J., Weber, R. P., Concannon, P., Hazelett, D. J., Li, Q., Marks, J. R., Berchuck, A., Lee, J. M., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., ... Schildkraut, J. M. (2015). Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer. Carcinogenesis, 36(11), 1341-1353. https://doi.org/10.1093/carcin/bgv138

Lawrenson, K, Iversen, ES, Tyrer, J, Weber, RP, Concannon, P, Hazelett, DJ, Li, Q, Marks, JR, Berchuck, A, Lee, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Plisiecka-Halasa, J, Dennis, J, Dicks, E, Doherty, JA, Dörk, T, du Bois, A, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Jakubowska, A, Paul, J, Jensen, A, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Cannioto, R, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Noor Azmi, MA, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Budzilowska, A, Sellers, TA, Shu, XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, SH, Terry, KL, Thompson, PJ, Timorek, A, Tworoger, SS, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, YL, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Coetzee, GA, Freedman, ML, Monteiro, ANA, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PD, Gayther, SA & Schildkraut, JM 2015, 'Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer', Carcinogenesis, vol. 36, no. 11, pp. 1341-1353. https://doi.org/10.1093/carcin/bgv138

@article{19908984ab6a46b1b1541a2c11e02532,

title = "Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer",

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.",

author = "Kate Lawrenson and Iversen, {Edwin S.} and Jonathan Tyrer and Weber, {Rachel Palmieri} and Patrick Concannon and Hazelett, {Dennis J.} and Qiyuan Li and Marks, {Jeffrey R.} and Andrew Berchuck and Lee, {Janet M.} and Aben, {Katja K.H.} and Hoda Anton-Culver and Natalia Antonenkova and Bandera, {Elisa V.} and Yukie Bean and Beckmann, {Matthias W.} and Maria Bisogna and Line Bjorge and Natalia Bogdanova and Brinton, {Louise A.} and Angela Brooks-Wilson and Fiona Bruinsma and Ralf Butzow and Campbell, {Ian G.} and Karen Carty and Jenny Chang-Claude and Georgia Chenevix-Trench and Ann Chen and Zhihua Chen and Cook, {Linda S.} and Cramer, {Daniel W.} and Cunningham, {Julie M.} and Cezary Cybulski and Joanna Plisiecka-Halasa and Joe Dennis and Ed Dicks and Doherty, {Jennifer A.} and Thilo D{\"o}rk and {du Bois}, Andreas and Diana Eccles and Easton, {Douglas T.} and Edwards, {Robert P.} and Ursula Eilber and Ekici, {Arif B.} and Fasching, {Peter A.} and Fridley, {Brooke L.} and Gao, {Yu Tang} and Aleksandra Gentry-Maharaj and Giles, {Graham G.} and Rosalind Glasspool and Goode, {Ellen L.} and Goodman, {Marc T.} and Jacek Gronwald and Philipp Harter and Hasmad, {Hanis Nazihah} and Alexander Hein and Florian Heitz and Hildebrandt, {Michelle A.T.} and Peter Hillemanns and Estrid Hogdall and Claus Hogdall and Satoyo Hosono and Anna Jakubowska and James Paul and Allan Jensen and Karlan, {Beth Y.} and Kjaer, {Susanne Kruger} and Kelemen, {Linda E.} and Melissa Kellar and Kelley, {Joseph L.} and Kiemeney, {Lambertus A.} and Camilla Krakstad and Diether Lambrechts and Sandrina Lambrechts and Le, {Nhu D.} and Lee, {Alice W.} and Rikki Cannioto and Arto Leminen and Jenny Lester and Levine, {Douglas A.} and Dong Liang and Jolanta Lissowska and Karen Lu and Jan Lubinski and Lene Lundvall and Massuger, {Leon F.A.G.} and Keitaro Matsuo and Valerie McGuire and McLaughlin, {John R.} and Heli Nevanlinna and Iain McNeish and Usha Menon and Francesmary Modugno and Moysich, {Kirsten B.} and Narod, {Steven A.} and Lotte Nedergaard and Ness, {Roberta B.} and {Noor Azmi}, {Mat Adenan} and Kunle Odunsi and Olson, {Sara H.} and Irene Orlow and Sandra Orsulic and Pearce, {Celeste L.} and Tanja Pejovic and Pelttari, {Liisa M.} and Jennifer Permuth-Wey and Phelan, {Catherine M.} and Pike, {Malcolm C.} and Poole, {Elizabeth M.} and Ramus, {Susan J.} and Risch, {Harvey A.} and Barry Rosen and Rossing, {Mary Anne} and Rothstein, {Joseph H.} and Anja Rudolph and Runnebaum, {Ingo B.} and Rzepecka, {Iwona K.} and Salvesen, {Helga B.} and Agnieszka Budzilowska and Sellers, {Thomas A.} and Shu, {Xiao Ou} and Shvetsov, {Yurii B.} and Nadeem Siddiqui and Weiva Sieh and Honglin Song and Southey, {Melissa C.} and Lara Sucheston and Tangen, {Ingvild L.} and Teo, {Soo Hwang} and Terry, {Kathryn L.} and Thompson, {Pamela J.} and Agnieszka Timorek and Tworoger, {Shelley S.} and {Van Nieuwenhuysen}, Els and Ignace Vergote and Vierkant, {Robert A.} and Shan Wang-Gohrke and Christine Walsh and Nicolas Wentzensen and Whittemore, {Alice S.} and Wicklund, {Kristine G.} and Wilkens, {Lynne R.} and Woo, {Yin Ling} and Xifeng Wu and Wu, {Anna H.} and Hannah Yang and Wei Zheng and Argyrios Ziogas and Coetzee, {Gerhard A.} and Freedman, {Matthew L.} and Monteiro, {Alvaro N.A.} and Joanna Moes-Sosnowska and Jolanta Kupryjanczyk and Pharoah, {Paul D.} and Gayther, {Simon A.} and Schildkraut, {Joellen M.}",

year = "2015",

month = nov,

day = "1",

doi = "10.1093/carcin/bgv138",

language = "English (US)",

volume = "36",

pages = "1341--1353",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "11",

}

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.

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

SN - 0143-3334

VL - 36

SP - 1341

EP - 1353

JO - Carcinogenesis

JF - Carcinogenesis

IS - 11

ER -

Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer

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