The effect of circulating proteins and their role in mediating adiposity’s effect on endometrioid and non-endometrioid endometrial cancer risk: Mendelian randomisation and colocalization analyses

Background: Proteomics could enhance our understanding of endometrial carcinogenesis. However, addressing confounding in traditional observational studies remains challenging, especially given the strong impact of adiposity on the plasma proteome and endometrial cancer risk. The role of circulating proteins in mediating adiposity’s effect on endometrial cancer risk is also not fully elucidated. Methods: Using Mendelian randomization (MR) and colocalization analyses, we examined the causal association between 2,751 unique proteins from UK Biobank (N Olink proteins=2,031; N=52,363) and deCODE (N SomaScan proteins=1,667; N=35,559) and endometrial cancer risk [overall (N cases=12,270; N controls=46,126), endometrioid (N cases=8,758), and non-endometrioid (N cases=1,230) in the meta-analysed Endometrial Cancer Association Consortium and Epidemiology of Endometrial Cancer Consortium data]. We performed enrichment analyses to explore pathways overrepresented among plasma proteins in endometrioid and non-endometrioid cancer subtypes. Additionally, we assessed the role of circulating proteins in mediating the effect of body mass index (BMI) on endometrial cancer risk using univariable and multivariable MR. Results: We identified 20 associations between circulating proteins and endometrial cancer risk in MR and colocalization analyses. GSTO1-1 and SKAP1 were positively associated and MMP10 was negatively associated with both overall and endometrioid endometrial cancer; DTYMK and ABO were positively associated and TSSC4 was negatively associated with overall endometrial cancer; IGF2R was positively associated with endometrioid cancer; MAPK9 was positively associated and DNAJB14, IFI16, LCN2, and SCT were negatively associated with non-endometrioid endometrial cancer. Distinct pathways were overrepresented in endometrioid (e.g., PDGF signalling and PTEN gene regulation) and non-endometrioid (e.g., non-canonical NF-kB signalling) cancer subtypes. GSTO1-1 and IGF2R were identified as potential mediators for the effect of BMI on endometrioid cancer risk in univariable MR, but evidence for mediation was not observed in multivariable MR analyses. Conclusions: We observed distinct plasma proteins and pathways associated with endometrioid and non-endometrioid endometrial cancers. These findings highlight candidate proteins for further mechanistic investigations, which could support the development of non-invasive methods to differentiate endometrial cancer subtypes and guide clinical intervention strategies. There was limited evidence that the effect of adiposity on endometrial cancer risk was mediated by circulating proteins examined in our study.