The Effect of Circulating Proteins and Their Role in Mediating Adiposity's Effect on Endometrial Cancer Risk: Mendelian Randomization and Colocalization Analyses

Sabrina E Wang ¹, Vanessa Y Tan ², James Yarmolinsky ³

⁰International Agency for Research on Cancer, World Health Organization, Lyon, France.

Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology +

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June 24, 2025

View abstract on PubMed

Summary

This study identified specific plasma proteins linked to different endometrial cancer subtypes using Mendelian randomization. These findings could aid in developing new methods for differentiating cancer types noninvasively.

Area Of Science

Genetics and Genomics
Oncology
Proteomics

Background

Proteomics offers potential for understanding endometrial carcinogenesis.
Observational studies face challenges in controlling for confounding factors like adiposity.
Adiposity significantly impacts both plasma proteome and endometrial cancer risk.

Purpose Of The Study

To investigate the causal relationship between plasma proteins and endometrial cancer risk.
To explore specific protein associations with endometrioid and non-endometrioid endometrial cancer subtypes.
To assess the mediating role of circulating proteins in the association between body mass index and endometrial cancer.

Main Methods

Mendelian randomization (MR) and colocalization analyses were employed.
Data from UK Biobank and deCODE datasets were utilized, analyzing 2,751 unique proteins.
Enrichment analyses identified overrepresented pathways in cancer subtypes.

Main Results

Twenty proteins showed associations with endometrial cancer risk.
Specific proteins were linked to overall, endometrioid, and non-endometrioid endometrial cancer.
Distinct pathways were identified for endometrioid and non-endometrioid cancer subtypes.

Conclusions

Distinct plasma proteins and pathways are associated with endometrioid and non-endometrioid endometrial cancer.
Identified proteins may facilitate noninvasive differentiation of endometrial cancer subtypes.