Causal Relationship Between 731 Immune Cell Phenotypes and Breast Cancer Subtypes: A Bidirectional Two-Sample Mendelian Randomization Study
10.3971/j.issn.1000-8578.2026.25.0909
- VernacularTitle:基于双向两样本孟德尔随机化的研究：探讨731种免疫细胞表型与乳腺癌亚型间的因果关系
- Author:
Tianci LIANG
1
;
Weicong LIANG
2
;
Yue ZHAO
1
;
Chenchen SONG
1
;
Tingzhi WEN
1
;
Hui WANG
1
;
Biaoxue RONG
3
Author Information
1. Department of Oncology, The First Affiliated Hospital of Xi’an Medical University, Xi’an 710077, China;Xi’an Medical University, Xi’an 710068, China.
2. Xi’an Medical University, Xi’an 710068, China;Department of Obstetrics and Gynecology, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an 710004, China.
3. Department of Oncology, The First Affiliated Hospital of Xi’an Medical University, Xi’an 710077, China.
- Publication Type:BASICRESEARCH
- Keywords:
Immune cells;
Breast cancer;
Mendelian randomization;
Causal association
- From:
Cancer Research on Prevention and Treatment
2026;53(6):448-456
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate the causal relationship between immune cells and various molecular subtypes of breast cancer (BC) by using two-sample Mendelian randomization (MR). Methods This study employed a two-sample MR analysis, with 731 immune cell types from the GWAS catalog as the exposure factors and four BC molecular subtypes (HR+/HER2−, HR+/HER2+, HR−/HER2+, and HR−/HER2−) from the BCAC Consortium as the outcome variables. For causal inference, inverse variance weighting (IVW) was employed as the primary analytical method, alongside multiple consistency validation approaches, including MR-Egger, weighted median, weighted mode, simple mode, and Bayesian weighted Mendelian randomization. Reverse MR and sensitivity analyses were employed to effectively evaluate and exclude potential biases and interference from reverse causality. Results Significant causal associations were identified for specific immune cell phenotypes across subtypes. In HR+ BC, the HER2+ subtype was associated with seven immunophenotypes (five protective and two risk increasing), whereas the HER2− subtype was associated with eight immunophenotypes (four protective and four risk increasing). In HR− BC, the HER2+ subtype was associated with five immunophenotypes (one protective and four risk increasing), and the HER2− subtype (triple-negative BC) was associated with seven immunophenotypes (six protective and one risk-increasing). CD28+CD45RA−CD8+ T cells and naive CD8+ T cells have a bidirectional causal relationship with HR+/HER2+ breast cancer, Whereas the expression of CD8 on CD39+CD8+ cells also has a bidirectional relationship with HR+/HER2− breast cancer. Furthermore, CD4−CD8− NKT cells exhibited opposing effect directions in HER2+ versus HER2− subtypes. Conclusion From a genetic perspective, this study confirms the existence of subtype-specific causal associations between immune cell phenotypes and distinct molecular subtypes of BC, revealing heterogeneity in immune regulation.
