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

Authors:
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

Carcinogenesis 2015 Nov 29;36(11):1341-53. Epub 2015 Sep 29.

Department of Community and Family Medicine, Duke University Medical Center, Durham, NC 27710, USA, Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC 27710, USA,

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.

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Source
http://dx.doi.org/10.1093/carcin/bgv138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635670PMC
November 2015
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