The tumor multi-omic landscape of endometrial cancers developed on a germline genetic background of adiposity

• Objective: This study used Mendelian randomization (MR) to investigate the causal effect of germline genetic risk for adiposity (BMI) on the multi-omic landscape (gene expression, somatic mutations, and immune microenvironment) of endometrial cancers (EC).
• Key Findings: Genetically predicted higher BMI was causally associated with increased expression of the oncogene MDM2 in EC tumors. It was also linked to a detrimental change in the tumor immune microenvironment, specifically decreasing CD4+ and cytotoxic T cell infiltration.
• Conclusion: The study suggests that germline adiposity fuels EC progression by promoting a more immunosuppressive tumor environment and activating key survival pathways, but not by altering the frequency of common somatic mutations.

PubMed: 37873386 DOI: 10.1101/2023.10.09.23296765 Overview generated by: Gemini 2.5 Flash, 28/11/2025

Key Findings: Linking Genetic Adiposity to Tumor Biology

This study used a two-sample Mendelian randomization (MR) approach to investigate how germline genetic variants associated with higher Body Mass Index (BMI)/adiposity causally influence the multi-omic landscape (gene expression, DNA methylation, somatic mutations, and tumor microenvironment) of subsequent endometrial cancers (EC).

• Causal Effect on Tumor Expression: Genetically predicted higher BMI was causally associated with increased expression of the gene MDM2 in EC tumors (FDR-corrected \(P < 0.05\)). MDM2 is a key regulator of the TP53 pathway and a potential oncogene, suggesting that the genetic effects of adiposity influence a critical tumor survival pathway.
• Tumor Immune Microenvironment (TIME) Effect: Higher genetically predicted BMI was also associated with significant changes in the tumor immune microenvironment. Specifically, it was causally linked to:
  • Decreased CD4+ T cell infiltration (\(P < 0.05\) FDR-corrected).
  • Decreased cytotoxic T cell infiltration (\(P < 0.05\) FDR-corrected).
  • This finding suggests that germline adiposity may drive EC progression by creating a more immunosuppressive tumor microenvironment, potentially reducing the efficacy of immunotherapies.
• No Causal Effect on Somatic Mutations: The study found no strong evidence that genetically predicted BMI causally influenced the frequency of common EC somatic mutations (e.g., in PTEN, PIK3CA, or TP53), indicating that the adiposity-driven mechanism likely impacts tumor biology through changes in gene expression and the TIME, rather than through altering fundamental mutation rates.

Study Design and Methods

Study Design

This was a two-sample Mendelian randomization (MR) study that integrated summary-level GWAS data for the exposure (adiposity) with tumor-specific multi-omic data from the outcome (EC tumor biology).

Data Sources and Exposures

• Exposure (Adiposity): Genetic variants (SNPs) associated with BMI were used as instrumental variables (IVs). A total of 170 independent BMI-associated SNPs were selected from a large GWAS meta-analysis (\(n=806,834\)).
• Outcome (EC Tumor Multi-omics): Multi-omic data for Endometrial Cancer (EC) were sourced from The Cancer Genome Atlas (TCGA) and other large consortia:
  • Transcriptomics: Gene expression levels for 17,929 genes.
  • Methylomics: DNA methylation levels across 11,108 CpG sites.
  • Somatic Mutations: Frequency of common driver mutations.
  • Tumor Microenvironment: Estimated immune cell infiltration levels (e.g., cytotoxic T cells, CD4+ T cells) derived from gene expression profiles using validated methods (e.g., CIBERSORT).

Statistical Analysis

1. Mendelian Randomization (MR): The Inverse-Variance Weighted (IVW) method was used as the primary MR approach to estimate the causal effect of genetically predicted BMI on each multi-omic feature. The results were reported as the change in the outcome feature per 1 standard deviation (SD) increase in BMI.
2. Sensitivity Analyses: Robust MR methods, including MR-Egger, were used to test for and account for potential horizontal pleiotropy.
3. Multiple Testing Correction: All results were subjected to a stringent False Discovery Rate (FDR) correction (Benjamini-Hochberg) to account for the large number of molecular outcomes tested (over 29,000 multi-omic traits).

Conclusions and Recommendations

The study concludes that a person’s germline genetic predisposition to adiposity plays a significant, causal role in shaping the molecular and immunological characteristics of their subsequent endometrial tumors.

• Mechanistic Insight: The findings suggest that the metabolic/endocrine consequences of adiposity (driven by the germline genome) likely fuel tumor growth by activating oncogenic pathways (MDM2 overexpression) and suppressing anti-tumor immunity (reduced CD4+ and cytotoxic T cell infiltration).
• Clinical Implications: This mechanistic understanding could inform targeted interventions. For instance, in individuals with high genetic adiposity risk, combining weight-loss interventions with treatments that counteract MDM2 activity or enhance T cell infiltration might prove particularly effective for EC prevention or therapy.
• Future Work: The authors recommend applying this multi-omic MR approach to investigate the causal influence of genetic adiposity on other obesity-related cancers (e.g., breast and colorectal cancer) and to explore the specific pathways driving the suppression of anti-tumor immunity.