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

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

AU - Australian Ovarian Cancer Study

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015/11

Y1 - 2015/11

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 (r (2) 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 (r (2) = 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 (r (2) 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 (r (2) = 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.

KW - Case-Control Studies

KW - Checkpoint Kinase 2

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Risk Factors

U2 - 10.1093/carcin/bgv138

DO - 10.1093/carcin/bgv138

M3 - SCORING: Journal article

C2 - 26424751

VL - 36

SP - 1341

EP - 1353

JO - CARCINOGENESIS

JF - CARCINOGENESIS

SN - 0143-3334

IS - 11

ER -