Zhang Yangyang, Lu Yangyuxiao, Wang Xuanyu, He Keren, Fang Mengqi, Xu Jiabao, Xu Ye, Tao Fangfang, Lü Ping
Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China.
The First Clinical Medical College, Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China.
J Cancer. 2024 Feb 4;15(7):1880-1889. doi: 10.7150/jca.92627. eCollection 2024.
Evidence suggests potential associations between gynecological malignancies and various immune cell chemicals and systems. However, establishing a causal relationship remains uncertain. This work employed Wald ratio for one single-nucleotide polymorphism (SNP) or the inverse-variance weighted method (IVW) for multiple SNPs to conduct bidirectional two-sample Mendelian randomization (MR) analysis by utilizing genome-wide association study (GWAS) data. We employed supplementary methods, including MR-Egger and weighted median methods, to detect and correct for the influence of horizontal pleiotropy. In addition, we also use colocalization analysis for further validation. In IVW analysis, increases in relative count of circulating CD11c HLA-DR conventional dendritic cells (cDC) were associated with an elevated risk of breast cancer (OR [95% CI], 1.1295 [1.0632-1.2000], P = 8.044 × 10), while elevated levels of HLA-DR on plasmacytoid dendritic cells (DC) and HLA-DR on DC were protective against breast cancer. In addition, actual count of CD39 resting Treg AC was also shown to be causally associated with the development of ovarian cancer, whereas a high relative count of CD28 CD45RA CD8 T cells reduced the risk of cervical cancer. Sensitivity analysis revealed almost no evidence of bias in the current study. Multivariable MR (MVMR) analyses further confirmed a direct impact of the CD11c HLA-DR cDC immune phenotype on breast cancer. Colocalization analysis showed the lead SNP, rs780094, suggesting HLA-DR GWAS shared a common genetic mechanism with breast cancer. The MR study identified significant causal relationships between multiple immunophenotypes and breast cancer, aiming to provide clinicians with some reference for cancer prediction and explore further potential associations between immune phenotypes and gynecologic tumors.
有证据表明妇科恶性肿瘤与各种免疫细胞化学物质和系统之间存在潜在联系。然而，确定因果关系仍不明确。本研究采用单核苷酸多态性（SNP）的Wald比或多个SNP的逆方差加权法（IVW），利用全基因组关联研究（GWAS）数据进行双向两样本孟德尔随机化（MR）分析。我们采用了补充方法，包括MR-Egger和加权中位数法，以检测和校正水平多效性的影响。此外，我们还使用共定位分析进行进一步验证。在IVW分析中，循环CD11c HLA-DR常规树突状细胞（cDC）相对计数增加与乳腺癌风险升高相关（OR [95% CI]，1.1295 [1.0632 - 1.2000]，P = 8.044 × 10），而浆细胞样树突状细胞（DC）上HLA-DR水平升高和DC上HLA-DR水平升高对乳腺癌具有保护作用。此外，CD39静息调节性T细胞AC的实际计数也被证明与卵巢癌的发生存在因果关系，而CD28 CD45RA CD8 T细胞的高相对计数降低了宫颈癌风险。敏感性分析显示本研究几乎没有偏差证据。多变量MR（MVMR）分析进一步证实了CD11c HLA-DR cDC免疫表型对乳腺癌的直接影响。共定位分析显示先导SNP rs780094，提示HLA-DR GWAS与乳腺癌共享共同遗传机制。MR研究确定了多种免疫表型与乳腺癌之间的显著因果关系，旨在为临床医生提供癌症预测的一些参考，并探索免疫表型与妇科肿瘤之间进一步的潜在关联。
