10 Years of GWAS discovery in endometrial cancer: Aetiology, function and translation

Wang, Xue Min; Glubb, Dylan M.; O’Mara, Tracy A.

doi:10.1016/j.ebiom.2022.103895

Cited by 16 publications

(14 citation statements)

References 80 publications

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“…Therefore, they are able to address some of the limitations of candidate gene studies, such as the insufficient coverage of variants in the selected genes as well as the identification of variants in unknown pathways [ 50 ]. GWAS also provides additional observations and inferences like identifying a genetic correlation between traits and determining confounding factors for disease development [ 51 ]. In the case of EC, a number of GWAS have been performed in the past that have led to the identification of new susceptibility loci and increased EC risk regions in the genome [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk

Das

Chaudhary

Tyagi

et al. 2023

Genes

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Endometrial cancer (EC) is among the most common gynecological disorders globally. As single nucleotide polymorphisms (SNPs) play an important role in the causation of EC, therefore, a comprehensive meta-analysis of 49 SNPs covering 25,446 cases and 41,106 controls was performed to identify SNPs significantly associated with increased EC risk. PubMed was searched to identify case control studies and meta-analysis was performed to compute the pooled odds ratio (OR) at 95% confidence interval (CI). Cochran’s Q-test and I2 were used to study heterogeneity, based on which either a random or a fixed effect model was implemented. The meta-analysis identified 11 SNPs (from 10 genes) to be significantly associated with increased EC risk. Among these, seven SNPs were significant in at least three of the five genetic models, as well as three of the polymorphisms (rs1801320, rs11224561, and rs2279744) corresponding to RAD51, PGR, and MDM2 genes, which contained more than 1000 EC cases each and exhibited increased risk. The current meta-analysis indicates that polymorphisms associated with various hormone related genes—SULT1A1 (rs1042028), PGR (rs11224561), and CYP19A1 (rs10046 and rs4775936); DNA repair genes—ERCC2 (rs1799793), OGG1 (rs1052133), MLH1 (rs1800734), and RAD51 (rs1801320) as well as genes like MDM2 (rs2279744), CCND1 (rs9344), and SERPINE1 (rs1799889), are significantly associated with increased EC risk.

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Section: Discussionmentioning

confidence: 99%

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk

Das

Chaudhary

Tyagi

et al. 2023

Genes

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“…[8][9][10] Splicing prediction analysis has yet to be integrated with GWAS data for many cancer types, including endometrial cancer (MIM: 608089). 11 sQTL discovery is expected to increase as well validated mapping methods are developed and long-read sequencing approaches are used. The incompleteness of current sQTL datasets means that some GWAS variants that affect splicing may not be revealed.…”

Section: Main Textmentioning

confidence: 99%

“…30 Obesity is a well-established risk factor for endometrial cancer, 31 and Mendelian randomization analyses have shown that increased body mass index and insulin levels are causally associated with endometrial cancer risk. 11 In contrast, individuals with neurofibromatosis type 1 have lower incidence of diabetes than healthy controls. 32; 33 Studies in model organisms have also suggested that NF1 loss protects against obesity, increasing the metabolic rate in Drosophila; 34 and reducing visceral and subcutaneous fat mass, and conferring protection from diet-induced obesity and hyperglycemia in mice.…”

Section: Main Textmentioning

confidence: 99%

Splicing annotation of endometrial cancer GWAS risk loci reveals potentially causal variants and supports a role forNF1andSKAP1as susceptibility genes

Canson

O’Mara

Spurdle

et al. 2022

Preprint

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Alternative splicing contributes to cancer development. Indeed, splicing analysis of cancer genome-wide association study (GWAS) risk variants has revealed likely causal variants. To systematically assess GWAS variants for splicing effects, we developed a prioritization workflow using a combination of splicing prediction tools, alternative transcript isoform and splicing quantitative trait locus (sQTL) annotations. Application of this workflow to candidate causal variants from 16 endometrial cancer GWAS risk loci highlighted single nucleotide polymorphisms (SNPs) that were predicted to upregulate alternative transcripts. For two variants, sQTL data supported the predicted impact on splicing. At the 17q11.2 locus, the protective allele for rs7502834 was associated with increased splicing of an exon inNF1alternative transcript encoding a truncated protein in adipose tissue and is consistent with an endometrial cancer transcriptome-wide association study (TWAS) finding in adipose tissue. Notably,NF1haploinsufficiency is protective for obesity, a well-established risk factor for endometrial cancer. At the 17q21.32 locus, the rs2278868 risk allele was predicted to upregulate aSKAP1transcript that is subject to nonsense mediated decay, concordant with a corresponding sQTL in lymphocytes. This is consistent with a TWAS finding that indicates decreasedSKAP1expression in blood increases endometrial cancer risk. As SKAP1 is involved in T-cell immune responses, decreasedSKAP1expression may impact endometrial tumor immunosurveillance. In summary, our analysis has identified potentially causal endometrial cancer GWAS risk variants with plausible biological mechanisms and provides a splicing annotation workflow to aid interpretation of other GWAS datasets.

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“… 9 A series of Mendelian randomization studies, which use trait-associated genetic variants to infer causal relationships, have confirmed known, and identified new, endometrial cancer risk factors. 10 These include increased body mass index (BMI), 6 , 11 , 12 early onset menarche, 6 , 13 low sex hormone binding globulin (SHBG), high testosterone, 14 increased serum estradiol, 15 increased fasting insulin, 11 and decreased low- (LDL) and increased high-density lipoprotein (HDL) cholesterol. 16 …”

Section: Introductionmentioning

confidence: 99%

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Wang¹,

Kho²,

Ramachandran³

et al. 2023

iScience

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10 Years of GWAS discovery in endometrial cancer: Aetiology, function and translation

Cited by 16 publications

References 80 publications

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk

Meta-Analysis of 49 SNPs Covering 25,446 Cases and 41,106 Controls Identifies Polymorphisms in Hormone Regulation and DNA Repair Genes Associated with Increased Endometrial Cancer Risk

Splicing annotation of endometrial cancer GWAS risk loci reveals potentially causal variants and supports a role forNF1andSKAP1as susceptibility genes

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

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