The effect of circulating proteins and their role in mediating adiposity’s effect on 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. Methods: Using Mendelian randomization (MR) and colocalization analyses, we examined the causal association between 2,751 unique proteins from the UK Biobank (N proteins=2,031; N=52,363) and deCODE (N proteins=1,667; N=35,559) with endometrial cancer risk [overall (N cases=12,270; N controls=46,126), endometrioid (N cases=8,758), and non-endometrioid (N cases=1,230)]. We performed enrichment analyses to explore pathways overrepresented among plasma proteins in endometrioid and non-endometrioid cancer subtypes. We assessed whether circulating proteins mediated the effect of body mass index (BMI) on endometrial cancer risk using univariable and multivariable MR. Results: 20 proteins were associated with endometrial cancer risk in MR and colocalization analyses. GSTO1-1 and SKAP1 were positively and MMP10 was negatively associated with overall and endometrioid endometrial cancer; DTYMK and ABO were positively and TSSC4 was negatively associated with overall endometrial cancer; IGF2R was positively associated with endometrioid cancer; MAPK9 was positively 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. There was weak evidence of associated proteins mediating the relationship between BMI and endometrial cancer risk. Conclusions: We identified distinct plasma proteins and pathways associated with endometrioid and non-endometrioid endometrial cancer risk. Impact: Prioritised proteins may support non-invasive methods to differentiate endometrial cancer subtypes.