Multi-tissue transcriptome-wide association study identifies eight candidate genes and tissue-specific gene expression underlying endometrial cancer susceptibility

Abstract

Genome-wide association studies (GWAS) have revealed sixteen risk loci for endoemtrial cancer but the identification of candidate susceptibility genes remains challenging. Here, we perform transcriptome-wide association study (TWAS) analyses using the largest endometrial cancer GWAS and gene expression from six relevant tissues, prioritizing eight candidate endometrial cancer susceptibility genes, one of which (EEFSEC) is located at a potentially novel endometrial cancer risk locus. We also show evidence of biologically relevant tissue-specific expression associations for CYP19A1 (adipose), HEY2 (ovary) and SKAP1 (whole blood). A phenome-wide association study demonstrates associations of candidate susceptibility genes with anthropometric, cardiovascular, diabetes, bone health and sex hormone traits that are related to endometrial cancer risk factors. Lastly, analysis of TWAS data highlights candidate compounds for endometrial cancer repurposing. In summary, this study reveals endometrial cancer susceptibility genes, including those with evidence of tissue specificity, providing insights into endometrial cancer aetiology and avenues for therapeutic development.

Lipid Metabolic-Related Signature CYP19A1 is a Potential Biomarker for Prognosis and Immune Cell Infiltration in Gastric Cancer

“…The role of CYP19A1 polymorphisms has been estimated in some types of cancers and diseases. [15][16][17][18][19] Gene mutations are extremely pivotal in tumor initiation and progression. 41 We also explored varying degrees of mutation in CYP19A1 in different GC cohort.…”

“…14 The role of CYP19A1 polymorphisms has been estimated in breast cancer, endometrial cancer, Alzheimer's, obesity, and cardiovascular disease. [15][16][17][18][19] To sum up, previous studies have focused on the polymorphism in CYP19A1 of which SNPs might be involved in the development and outcome of various cancers and diseases. However, some of the results are inconsistent on account of the location of tumors and survival rate of the patients.…”

Prognostic and Diagnostic Values of Semaphorin 5B and Its Correlation With Tumor-Infiltrating Immune Cells in Kidney Renal Clear-Cell Carcinoma

“…Our findings demonstrate that SEMA5B was highly positively correlated with the top six co-expressed genes (PDIA5, ACAD11, SLC25A34, EEFSEC, IFT122, and SLC23A3), and five of these genes served as a protective factor for the favorable survival of KIRC. However, some of these genes have been reported to act as poor prognosis in malignancy ( Kho et al, 2021 ; Zhang et al, 2021 ). To further explore the potential oncogenic mechanism of SEMA5B action, we conducted the GO and KEGG analyses of the co-expressed genes.…”

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

“… b Number of cell lines HiChIP chromatin looping observed provided in parentheses; references for functional studies are provided; pan-cancer driver genes are those listed in Bailey et al. 56 ; TWAS genes, eQTLs and HiChIP targets are those reported using data from Kho et al., 49 O'Mara et al 46 and Glubb et al. 38 …”

“…Using this multi-tissue TWAS approach, in conjunction with prioritisation by colocalisation or Mendelian randomisation analyses, eight candidate endometrial cancer susceptibility genes have been identified. 49 Seven of the eight candidate susceptibility genes were located at endometrial cancer GWAS susceptibility loci, with the novel candidate susceptibility gene EEFSEC located at a potentially novel risk locus ( Table 3 ). Importantly, these approaches have allowed the identification of tissue specific associations.…”