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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 (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.

SUBMITTER: Lawrenson K

PROVIDER: S-EPMC4635670 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

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

Carcinogenesis 20150929 11

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 a ...[more]

PMID: 26424751

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Project description:BACKGROUND:Mitochondria are the site of oxidative phosphorylation, a process which generates reactive oxygen species (ROS). Elevated ROS levels can lead to oxidative stress, a cellular state implicated in carcinogenesis. It is hypothesized that alternations in mitochondrial (MT) DNA, including heritable MT single nucleotide polymorphisms (MT-SNPs), have the potential to change the capacity of MT function, leading to increased oxidative stress and cancer risk. We investigated if common MT-SNPs and/or haplogroups and are associated with invasive serous ovarian cancer (OvCa) risk. METHODS:A panel of 64 MT-SNPs designed to tag all common variation in the European MT genome (minor allele frequency (MAF) >1%, r^2 >0.8) was genotyped in study participants of European descent using the Sequenom MassARRAY iPlex Gold® system (Sequenom Inc, CA, USA). Invasive serous OvCa cases (n?=?405) and frequency age-matched controls (n?=?445) were drawn from a population-based case-control study of OvCa in western Canada. Binary logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (C.I.) for carriage of the minor versus major allele by case-control status. MitoTool was used to test the relationship between European haplogroup status and case-control status using Fisher's exact test. RESULTS:The most significant disease-SNP association was for rs2857285, a synonymous MT-SNP in ND4 (OR?=?4.84, 95% CI: 1.03-22.68, P?=?0.045). After adjustment for multiple testing using a Bonferroni correction of the Type 1 error this MT-SNP was not significant. No other MT-SNP had a P-value?<?0.05. European haplogroup status was not associated with case status. Most MT-SNPs (73%) genotyped had a MAF <5%. CONCLUSION:Common European MT-SNPs (MAF?>?5%) and haplogroups were not associated with invasive serous OvCa risk in this study; however, most European MT-SNPs have a low MAF (<5%), which we were underpowered to adequately assess. Larger studies are needed to clarify the role of low MAF MT-SNPs (MAF?<?5%) in invasive serous OvCa risk.

Project description:ImportanceCHEK2 pathogenic and likely pathogenic variants (PVs) are common, and low-risk (LR) variants, p.I157T, p.S428F, and p.T476M, are even more common. Biallelic CHEK2 PVs are associated with specific cancer phenotypes, including early age at onset of breast cancers. Whether biallelic LR variants are associated with cancer predisposition is unknown.ObjectiveTo characterize the cancer phenotype among individuals with biallelic CHEK2 variants, specifically those that have been associated with lower cancer risk in the heterozygous state.Design, setting, and participantsThis retrospective observational cohort study examining cancer phenotype by CHEK2 genotype was conducted at a single diagnostic genetic testing laboratory. Of 36 821 individuals who underwent genetic testing, 3783 (10.3%) with CHEK2 PVs or LR variants were ascertained from July 1, 2012, to September 30, 2019. Analyses were conducted from September 2022 to January 2024.ExposuresCancer phenotype among individuals with 2 LR variants and those with 1 PV and 1 LR variant was compared with cancer phenotype among individuals with wild type (WT) (n = 33 034), single LR variant (n = 1566), single PV controls (n = 2167), and 2 PVs (n = 21). Cancer phenotypes were investigated for any cancer, multiple primary cancers, female breast cancer, and bilateral female breast cancers.Main outcomes and measuresCancer phenotype of CHEK2 2 LRs and 1 PV and 1 LR.ResultsOf 36 821 individuals, 92.1% were female, and the median age at testing was 53 years (IQR, 44-63 years); 3787 (10.3%) were identified as having a CHEK2 PV or LR variant. There were 13 individuals with 2 LR variants and 20 with 1 PV and 1 LR variant. Among those with 2 LR variants, prevalence of any cancer (76.9%) and breast cancer (60.0%) were similar to those with WT (any cancer, 69.8%; breast cancer, 52.7%) and those with a single LR variant (any cancer, 70.9%; breast cancer, 57.5%). Among participants with 1 PV and 1 LR variant, 95.0% had a prior cancer diagnosis, a higher rate than among those with a single PV (76.8%), but the difference was not statistically significant. Among female individuals with 1 PV and 1 LR variant, 86.7% had a breast cancer diagnosis, compared with 67.1% with a single PV, although these differences were not statistically significant.Conclusions and relevanceIn this cohort study, individuals with 2 LR variants in CHEK2 had a cancer phenotype similar to those with a single LR variant and similar to WT controls. Individuals with 1 PV and 1 LR variant may have a more penetrant cancer phenotype than individuals with a single PV. Future studies focused on CHEK2 LR variants will aid in better understanding whether these variants are genetic modifiers associated with cancer risk.

Project description:BackgroundDefective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.MethodsIn total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.ResultsThe most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).ConclusionThese results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Project description:BackgroundBreast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas.MethodsWe performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach.ResultsWe identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017).ConclusionOur study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.

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

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

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