Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Kho, Pik Fang; Amant, Frédéric; Annibali, Daniela; Ashton, Katie A.; Attia, John; Auer, Paul L.; Beckmann, Matthias W.; Black, Amanda; Brinton, Louise A.; Buchanan, Daniel D.; Chanock, Stephen J.; Chen, Chu; Chen, Maxine M.; Cheng, Timothy; Cook, Linda S.; Crous‐Bou, Marta; Czene, Kamila; Vivo, Immaculata De; Dennis, Joe; Dörk, Thilo; Dowdy, Sean C.; Dunning, Alison M.; Dürst, Matthias; Easton, Douglas F.; Ekici, Arif B.; Fasching, Peter A.; Fridley, Brooke L.; Friedenreich, Christine M.; García‐Closas, Montserrat; Gaudet, Mia M.; Giles, Graham G.; Goode, Ellen L.; Gorman, Maggie; Haiman, Christopher A.; Hall, Per; Hankinson, Susan E.; Hein, Alexander; Hillemanns, Peter; Hodgson, Shirley; Høivik, Erling A.; Holliday, Elizabeth G.; Hunter, David J.; Jones, Angela; Kraft, Peter; Krakstad, Camilla; Lambrechts, Diether; Marchand, Loı̈c Le; Liang, Xiaolin; Lindblom, Annika; Lissowska, Jolanta; Long, Jirong; Lu, Lingeng; Magliocco, Anthony M.; Martin, Lynn; McEvoy, Mark; Milne, Roger L.; Mints, Miriam; Nassir, Rami; Otton, Geoffrey; Palles, Claire; Pooler, Loreall; Proietto, Tony; Rebbeck, Timothy R.; Renner, S.; Risch, Harvey A.; Rübner, Matthias; Runnebaum, I. B.; Sacerdote, Carlotta; Sarto, Gloria E.; Schumacher, Fredrick R.; Scott, Rodney J.; Setiawan, Veronica Wendy; Shah, Mitul; Sheng, Xin; Shu, Xiao Ou; Southey, Melissa C.; Tham, Emma; Tomlinson, Ian; Trovik, Jone; Turman, Constance; Tyrer, Jonathan P.; Berg, David Van Den; Wang, Zhaoming; Wentzensen, Nicolas; Xia, Lucy; Xiang, Yong Bing; Yang, Hannah; Yu, Herbert; Wang, Zheng; Webb, Penelope M.; Thompson, Deborah J.; Spurdle, Amanda B.; Glubb, Dylan M.; O’Mara, Tracy A.

doi:10.1002/ijc.33206

Cited by 49 publications

(52 citation statements)

References 44 publications

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“…Equally importantly, every newly identified region adds to our knowledge about the etiology of the disease and can point to possible pharmacological targets. In addition, single nucleotide polymorphism genotypes have already proven very helpful in corroborating epidemiological and clinical observations by detecting potentially causal relationships between physiological traits and endometrial cancer through Mendelian randomization analyses [ 27 , 94 , 95 , 96 , 97 ].…”

Section: Risk Factors Biology and Geneticsmentioning

confidence: 99%

Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

Dörk

Hillemanns

Tempfer

et al. 2020

Cancers

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Endometrial cancer (EC) is the most common cancer affecting the female reproductive organs in higher-income states. Apart from reproductive factors and excess weight, genetic predisposition is increasingly recognized as a major factor in endometrial cancer risk. Endometrial cancer is genetically heterogeneous: while a subgroup of patients belongs to cancer predisposition syndromes (most notably the Lynch Syndrome) with high to intermediate lifetime risks, there are also several common genomic polymorphisms contributing to the spectrum of germline predispositions. Germline variants and somatic events may act in concert to modulate the molecular evolution of the tumor, where mismatch-repair deficiency is common in endometrioid endometrial tumors whereas homologous recombinational repair deficiency has been described for non-endometrioid endometrial tumors. In this review, we will survey the currently known genomic predispositions for endometrial cancer and discuss their relevance for clinical management in terms of counseling, screening and novel treatments.

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Section: Risk Factors Biology and Geneticsmentioning

confidence: 99%

Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

Dörk

Hillemanns

Tempfer

et al. 2020

Cancers

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“…GWAS data for these traits could be used to assess their effects on endometrial cancer risk using similar Mendelian randomisation approaches to our studies of body mass index and blood lipids (Kho et al, 2020;.…”

Section: Discussionmentioning

confidence: 99%

“…Another phenotypic category contained cardiovascular traits (e.g. ischaemic heart disease and systolic blood pressure) which are associated with genetically established endometrial cancer risk factors such as body mass index, LDL and HDL cholesterol (Kho et al, 2020; O’Mara, Glubb, et al, 2019). These findings suggest that the identified traits belonging to the remaining phenotypic categories (liver function and haematopoiesis) may provide novel insights into endometrial cancer aetiology.…”

Section: Discussionmentioning

confidence: 99%

“…These findings suggest that the identified traits belonging to the remaining phenotypic categories (liver function and haematopoiesis) may provide novel insights into endometrial cancer aetiology. GWAS data for these traits could be used to assess their effects on endometrial cancer risk using similar Mendelian randomisation approaches to our studies of body mass index and blood lipids (Kho et al, 2020; O’Mara, Glubb, et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility

Kho

Partida

Dörk

et al. 2020

Preprint

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Genome-wide association studies (GWAS) of endometrial cancer have identified 16 genetic susceptibility loci. To identify candidate endometrial cancer susceptibility genes, we have performed the first transcriptome-wide association study (TWAS) of endometrial cancer. For this analysis, we have used the largest endometrial cancer GWAS and gene expression from 48 tissues to maximise statistical power. We used colocalisation analysis to prioritise seven candidate susceptibility genes, including CYP19A1, which wes previously established as an endometrial cancer susceptibility gene. Notably, one of the candidate susceptibility genes was located at 17q24.2, a potentially novel risk locus for endometrial cancer. Using phenome-wide association analysis, candidate susceptibility genes were found to associate with traits related to endometrial cancer risk factors, in addition to other clinical phenotypes that may provide novel risk factors. TWAS data were also used to perform drug repurposing analysis and identified 14 compounds; two of these are tubulin inhibitors, a drug class used to treat advanced endometrial cancer. In summary, this study has revealed biologically relevant endometrial cancer susceptibility genes, providing insights into endometrial cancer aetiology and avenues for the development of new treatments.

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“…Adjustment for BMI was conducted by fitting the female-stratified UK Biobank GWAS summary statistics of BMI as a covariate of the analysis of endometrial cancer using GWAS summary-level data using the mtCOJO method 21 implemented in GCTA (version 1.91.7beta) 22 . Linkage disequilibrium (LD) was estimated using individual genotypic data from a random set of 10,000 unrelated individuals from the UK Biobank cohort (https://www.ukbiobank.ac.uk/) selected by Kho et al (2020) 14 .…”

Section: Genetic Correlationmentioning

confidence: 99%

Multi-trait genome-wide association study identifies novel endometrial cancer risk loci that are associated with obesity or female testosterone levels

Wang

Kho

Ramachandran

et al. 2021

Preprint

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We have performed genetic correlation and Mendelian randomization analyses using publicly available genome-wide association study (GWAS) data to identify endometrial cancer risk factors. These and previously established risk factors of endometrial cancer were then included in a multi-trait Bayesian GWAS analysis to detect endometrial cancer susceptibility variants, identifying three novel loci (7q22.1, 8q24.3 and 16q12.2); two of which were replicated in an independent endometrial cancer GWAS dataset. These loci are hypothesized to affect endometrial cancer risk through altered sex-hormone levels or through effects on obesity. Consistent with this hypothesis, several genes with established roles in these pathways (CYP11B1, CYP3A7, IRX3 and IRX5) were prioritized as candidate endometrial cancer risk genes by interrogation of quantitative trait loci data and chromatin capture assays in endometrial cell lines. The findings of this study identify additional opportunities for hormone treatment and further support weight loss to reduce the risk of developing endometrial cancer.

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Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Cited by 49 publications

References 44 publications

Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management

Multi-tissue transcriptome-wide association study identifies genetic mechanisms underlying endometrial cancer susceptibility

Multi-trait genome-wide association study identifies novel endometrial cancer risk loci that are associated with obesity or female testosterone levels

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