CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Thompson, Deborah J.; O’Mara, Tracy A.; Glubb, Dylan M.; Painter, Jodie N.; Cheng, Timothy; Folkerd, Elizabeth; Doody, Deborah; Dennis, Joe; Webb, Penelope M.; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Michailidou, Kyriaki; Tyrer, Jonathan P.; Maranian, Mel; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Ekici, Arif B.; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B.; Zhao, Hui; Depreeuw, Jeroen; Schrauwen, Stefanie; Amant, Frédéric; Goode, Ellen L.; Fridley, Brooke L.; Dowdy, Sean C.; Winham, Stacey J.; Salvesen, Helga B.; Trovik, Jone; Njølstad, Tormund S.; Werner, Henrica M.J.; Ashton, Katie A.; Proietto, Tony; Otton, Geoffrey; Carvajal‐Carmona, Luis G.; Tham, Emma; Liu, Tao; Mints, Miriam; Scott, Rodney J.; McEvoy, Mark; Attia, John; Holliday, Elizabeth G.; Montgomery, Grant W.; Martin, Nicholas G.; Nyholt, Dale R.; Henders, Anjali K.; Hopper, John L.; Traficante, Nadia; Ruebner, Matthias; Swerdlow, Anthony; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Lambrechts, Diether; Chang‐Claude, Jenny; Couch, Fergus J.; Giles, Graham G.; Kristensen, Vessela N.; Cox, Angela; Bolla, Manjeet K.; Wang, Qin; Bojesen, Stig E.; Shah, Mitul; Luben, Robert; Khaw, Kay‐Tee; Pharoah, Paul D.P.; Dunning, Alison M.; Tomlinson, Ian; Dowsett, Mitchell; Easton, Douglas F.; Spurdle, Amanda B.

doi:10.1530/erc-15-0386

Cited by 65 publications

(84 citation statements)

References 46 publications

(62 reference statements)

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“…Finally, there are similarities in tumor phenotype and/or shared tissue of origin between endometrial cancer, the benign gynaecological condition endometriosis, the endometrioid and clear cell histologies of ovarian cancer, and basal-like breast cancer(25–27). Thus, pooling ovarian and endometrial(23, 28, 29) cases could uncover novel loci.…”

Section: Methodsmentioning

confidence: 99%

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Amos

Dennis

Wang

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact Ongoing analyses will shed light on etiology and risk assessment for many types of cancer.

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Section: Methodsmentioning

confidence: 99%

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Amos

Dennis

Wang

et al. 2017

Cancer Epidemiology, Biomarkers &Amp; Prevention

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312

380

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“…Previously, meta-analysis of data for 7,737 endometrial cancer cases and 37,144 controls of European ancestry from three GWAS datasets (ANECS, SEARCH, and NSECG) and two followup datasets (iCOGs and NSECG Phase 2) identified rs2498796 (OR ¼ 1.12 for the minor A allele, 95% CI:1.07-1.17, p value ¼ 3.55 3 10 À8 ) as the top SNP representing a single association signal at the 14q32.33 endometrial cancer risk locus. 6 For the current study we employed an in silico fine-mapping approach 12 previously used to fine-map other endometrial cancer risk loci, 4,5,13,14 focussing on the 1Mb region surrounding rs2498796 (bases 104,743,220-105,743,220; NCBI build 37/hg19 assembly). The current analysis utilized genotyped and imputed SNP data for the three GWAS (ANECS, SEARCH, and NSECG) and the iCOGs follow-up datasets and included a total of 6,608 endometrial cancer cases and 37,925 controls (details of these datasets can be found in 4,5 ).…”

Section: Methodsmentioning

confidence: 99%

“…6 For the current study we employed an in silico fine-mapping approach 12 previously used to fine-map other endometrial cancer risk loci, 4,5,13,14 focussing on the 1Mb region surrounding rs2498796 (bases 104,743,220-105,743,220; NCBI build 37/hg19 assembly). The current analysis utilized genotyped and imputed SNP data for the three GWAS (ANECS, SEARCH, and NSECG) and the iCOGs follow-up datasets and included a total of 6,608 endometrial cancer cases and 37,925 controls (details of these datasets can be found in 4,5 ). The Cheng et al analysis had included a total of 420 genotyped and imputed SNPs with minor allele frequencies (MAF) R1% and information scores R0.9 per dataset within the focal region.…”

Section: Methodsmentioning

confidence: 99%

“…Endometrial cancer (MIM: 608089) (cancer of the lining of the uterine corpus) is the fourth most diagnosed cancer in women in Europe and North America. 1,2 To date, analyses of multiple genome-wide association study (GWAS) and follow-up datasets, comprising up to 7,737 endometrial cancer cases and 37,144 controls, have identified seven risk loci at genome-wide significance for this disease, including HNF1B (MIM: 189907), 3,4 CYP19A1 (MIM: 107910), 5 and novel loci on chromosomes 13q22.1, 6q22.31, 8q24.21, 15q15.1, and 14q32.33. 6 The lead SNP at the 14q32.33 locus, rs2498796, represents a single association signal located in the region of the AKT1 (MIM: 164730) oncogene.…”

Section: Introductionmentioning

confidence: 99%

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A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

Painter

Kaufmann

O’Mara

et al. 2016

The American Journal of Human Genetics

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A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.

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“…The CYP19A1 gene is located on the chromosome 15 at 15q21.2 and it mainly encodes CYPs aromatase, which involves converting testosterone to estradiol and androstenedione to estrone respectively [5,6]. Most studies of the CYP19A1 gene are about hormone-related cancers, such as the breast cancer, prostate cancer, and endometrial cancer, and some research of them found that they are directly related to endogenous and exogenous steroid hormones that affect cell proliferation [7][8][9][10]. These results suggest that CYP19A1 gene may be associated with the development of tumors.…”

Section: Introductionmentioning

confidence: 99%

Association of CYP19A1 Polymorphism with Genetic Susceptibility to Lung Cancer in Chinese population:a case-control study

et al. 2019

Preprint

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Background Lung cancer is a kind of cancer with high morbidity and mortality related to genetic factors. Many studies have shown that CYP19A1 gene polymorphism is associated with a variety of cancers, but there are few studies on lung cancer at present. The aim of the study was to explore the correlation between CYP19A1 polymorphisms and lung cancer risk in Chinese population.Methods We enrolled 510 lung cancer patients as the case group and 504 healthy people as the control group. Five single nucleotide polymorphisms determined in CYP19A1 gene were genotyped by MassARRAY, and correlation analysis was performed by Chi square test and logistic regression model.Results The genotypes of rs4646 (OR=0.77, p=0.010), rs6493487 (OR=0.76, p=0.006) and rs17601876 (OR=0.69, p=1.15E-04) in CYP19A1 gene were linked to decreasing the risk of lung cancer, while the rs1062033 (OR=1.49, p=0.029) was linked to increasing lung cancer risk. In gender-stratified analysis, female patients with the GG genotype of the rs6493487 (OR=0.31, p=0.037) and male patients with the rs17601876 (OR=0.52, p=0.012) had lower lung cancer risk. In age-stratified analysis, for patients ≥58 years, decreased lung cancer risk was correlated with the genotypes of rs4646 (OR=0.66, p=0.021), rs6493487 (OR=0.65, p=0.021) and rs17601876 (OR=0.39, p=0.001), and increased risk was associated with the GG genotype of rs1062033 (OR=2.09, p=0.003). In pathologic type-stratified analysis, the AA genotype of rs17601876 (OR=0.41, p=0.048) was associated with decreased risk of small cell lung cancer, and the AA genotype of rs4646 (OR=0.41, p=0.027), the GA genotype of rs6493487 (OR=0.65, p=0.024) and the AA genotype of rs17601876 (OR=0.34, p=0.005) were linked to decreased risk of squamous cell carcinoma.Conclusion CYP19A1 polymorphisms are associated with lung cancer risk, especially in elderly patients and patients with pathologic types of small cell lung cancer and squamous cell carcinoma.

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CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Cited by 65 publications

References 46 publications

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding

Association of CYP19A1 Polymorphism with Genetic Susceptibility to Lung Cancer in Chinese population:a case-control study

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