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Background <p>Polycystic kidney disease 1 (PKD1) has emerged as a potential oncogene in various malignancies, but its causal relationship with endometrial cancer risk and clinical outcomes remains unclear. This study employed Mendelian randomization (MR) analysis to investigate the causal effects of gene expression on endometrial cancer susceptibility, with comparative analysis to renal cell carcinoma, focusing on PKD1’s functional role.</p> Methods <p>We conducted a comprehensive summary-data-based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) from CAGE sparse tissue dataset as instrumental variables. The analysis examined 30 candidate genes for endometrial cancer and 29 genes for renal cancer risk using UK Biobank GWAS data. Cross-cancer comparative analysis identified shared susceptibility genes between both malignancies. PKD1’s role was further characterized through correlation network analysis, immune cell infiltration profiling, and Cox regression survival analysis in 553 endometrial cancer patients. Experimental validation was performed using qRT-PCR in representative cancer cell lines compared to normal controls.</p> Results <p>SMR analysis revealed modest but statistically significant causal effects for multiple genes on both cancer types (p_SMR &lt; 0.05), with odds ratios clustering around 1.0. Comparative analysis between renal cancer (220 genes) and endometrial cancer (196 genes) identified only 12 shared susceptibility genes (2.8% overlap) including EP300, CKB, NME7, and TATDN3, highlighting distinct genetic architectures. PKD1 correlation network analysis in endometrial cancer demonstrated positive associations with PET100, AC093899.1, and PDE4DIPP1. Importantly, PKD1 expression levels significantly influenced tumor immune microenvironment composition, with PKD1-low endometrial tumors showing enhanced infiltration of myeloid dendritic cells, T helper cells, and Th1 cells (<i>p</i> &lt; 0.05). However, Cox regression analysis revealed that PKD1 expression did not impact patient survival outcomes (HR = 1.020, 95% CI: 0.681–1.529, <i>p</i> = 0.923), while clinical stage and primary therapy outcome remained significant prognostic factors.</p> Conclusions <p>This multi-cancer Mendelian randomization study provides evidence for largely distinct genetic landscapes between renal and endometrial cancers, with minimal gene overlap. PKD1 demonstrates a novel dual role in endometrial cancer pathogenesis.</p>

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Mendelian randomization analysis of PKD1 in endometrial cancer and comparative multi-cancer study with renal cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Xuecheng Pang,
  • Yu Wang,
  • Qiang Zhang,
  • LiJie Gu

摘要

Background

Polycystic kidney disease 1 (PKD1) has emerged as a potential oncogene in various malignancies, but its causal relationship with endometrial cancer risk and clinical outcomes remains unclear. This study employed Mendelian randomization (MR) analysis to investigate the causal effects of gene expression on endometrial cancer susceptibility, with comparative analysis to renal cell carcinoma, focusing on PKD1’s functional role.

Methods

We conducted a comprehensive summary-data-based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) from CAGE sparse tissue dataset as instrumental variables. The analysis examined 30 candidate genes for endometrial cancer and 29 genes for renal cancer risk using UK Biobank GWAS data. Cross-cancer comparative analysis identified shared susceptibility genes between both malignancies. PKD1’s role was further characterized through correlation network analysis, immune cell infiltration profiling, and Cox regression survival analysis in 553 endometrial cancer patients. Experimental validation was performed using qRT-PCR in representative cancer cell lines compared to normal controls.

Results

SMR analysis revealed modest but statistically significant causal effects for multiple genes on both cancer types (p_SMR < 0.05), with odds ratios clustering around 1.0. Comparative analysis between renal cancer (220 genes) and endometrial cancer (196 genes) identified only 12 shared susceptibility genes (2.8% overlap) including EP300, CKB, NME7, and TATDN3, highlighting distinct genetic architectures. PKD1 correlation network analysis in endometrial cancer demonstrated positive associations with PET100, AC093899.1, and PDE4DIPP1. Importantly, PKD1 expression levels significantly influenced tumor immune microenvironment composition, with PKD1-low endometrial tumors showing enhanced infiltration of myeloid dendritic cells, T helper cells, and Th1 cells (p < 0.05). However, Cox regression analysis revealed that PKD1 expression did not impact patient survival outcomes (HR = 1.020, 95% CI: 0.681–1.529, p = 0.923), while clinical stage and primary therapy outcome remained significant prognostic factors.

Conclusions

This multi-cancer Mendelian randomization study provides evidence for largely distinct genetic landscapes between renal and endometrial cancers, with minimal gene overlap. PKD1 demonstrates a novel dual role in endometrial cancer pathogenesis.