Causal associations between immune cell phenotypes and HER genes of breast cancer based on Mendelian randomization_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIU Wenyan ¹ , DU Kaihao ¹ , WANG Wei ¹ ,  MA Zhijun ²

1. School of Clinical Medicine, Qinghai University, Xining 810000, P. R. China;
2. Department of Oncology, Affiliated Hospital of Qinghai University, Xining 810000, P. R. China;

Corresponding author：

MA Zhijun, Email: mzjfamai@163.com

Keywords：

breast cancer; immune cell phenotype; Mendelian randomization

DOI：

10.7507/1007-9424.202412015

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the causal relationship between 731 kinds of immune cells and positive-human epidermal growth factor receptor (HER⁺), negative-human epidermal growth factor receptor (HER^–), negative-human epidermal growth factor receptor 2 (HER2^–) breast cancer. Methods Genome-wide association data for immune cells and breast cancer were used, and using inverse variance weighting as the primary analytical method, and Cochran’s Q test, Mendelian randomization (MR)-Egger regression, and leave-one-out were used to verify the reliability of the resulting data. Results For HER⁺ breast cancer, CD3 on CD39⁺CD4⁺T cell [IVW: OR=0.940, 95%CI (0.913, 0.968), P<0.01], ratio of CD4^–CD8^–T cell [IVW: OR=0.906, 95%CI (0.857, 0.958), P<0.01], and CD3 on secreting CD4 regulatory T cell [IVW: OR=0.948, 95%CI (0.918, 0.979), P=0.01] were protective factors. For HER^– breast cancer, no immune cell phenotype was found to be correlated with it. For HER2^– breast cancer, CD3 on CD39⁺CD4⁺ T cell [IVW: OR=0.951, 95%CI (0.930, 0.973), P<0.01], CD3 on secreting CD4 regulatory T cell [IVW: OR=0.949, 95% CI (0.925, 0.974), P<0.01] were protective factors. Conclusion There is a causal association between certain immune cell phenotypes and breast cancer, which may be a predictive marker for early diagnosis of breast cancer and development of new immunotherapies.

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5.	Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 2023, 23(1): 590.
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11.	Zhou X, Yu L, Wang L, et al. Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study. Eur J Epidemiol, 2022, 37(7): 701-712.
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17.	陈洁, 彭榆富. 乳腺癌的免疫治疗进展. 中国普外基础与临床杂志, 2019, 26(12): 1403-1408.
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19.	Wang Z, Yang X, Shen J, et al. Gene expression patterns associated with tumor-infiltrating CD4⁺ and CD8⁺ T cells in invasive breast carcinomas. Hum Immunol, 2021, 82(4): 279-287.
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24.	Hu XE, Yang P, Chen S, et al. Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low. Breast Cancer Res, 2023, 25(1): 34.
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26.	Kortekaas KE, Santegoets SJ, Sturm G, et al. CD39 identifies the CD4⁺ tumor-specific T-cell population in human cancer. Cancer Immunol Res, 2020, 8(10): 1311-1321.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Dieci MV, Miglietta F, Guarneri V. Immune infiltrates in breast cancer: recent updates and clinical implications. Cells, 2021, 10(2): 223.
3. Wade KH, Yarmolinsky J, Giovannucci E, et al. Applying Mendelian randomization to appraise causality in relationships between nutrition and cancer. Cancer Causes Control, 2022, 33(5): 631-652.
4. Orrù V, Steri M, Sidore C, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet, 2020, 52(10): 1036-1045.
5. Wang C, Zhu D, Zhang D, et al. Causal role of immune cells in schizophrenia: Mendelian randomization (MR) study. BMC Psychiatry, 2023, 23(1): 590.
6. Gkatzionis A, Burgess S, Newcombe PJ. Statistical methods for cis-Mendelian randomization with two-sample summary-level data. Genet Epidemiol, 2023, 47(1): 3-25.
7. Carter AR, Sanderson E, Hammerton G, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol, 2021, 36(5): 465-478.
8. Choi HG, Park JH, Choi YJ, et al. Association of family history with the development of breast cancer: a cohort study of 129, 374 Women in KoGES data. Int J Environ Res Public Health, 2021, 18(12): 6409.
9. Elghazawy H, Bakkach J, Zaghloul MS, et al. Implementation of breast cancer continuum of care in low- and middle-income countries during the COVID-19 pandemic. Future Oncol, 2020, 16(31): 2551-2567.
10. Drummond AE, Swain CTV, Brown KA, et al. Linking physical activity to breast cancer via sex steroid hormones, part 2: the effect of sex steroid hormones on breast cancer risk. Cancer Epidemiol Biomarkers Prev, 2022, 31(1): 28-37.
11. Zhou X, Yu L, Wang L, et al. Alcohol consumption, blood DNA methylation and breast cancer: a Mendelian randomisation study. Eur J Epidemiol, 2022, 37(7): 701-712.
12. Beck MH, Brachaczek IA, Gebert P, et al. Incidence of seroma and postoperative complications after breast surgery before and during the Covid-19 pandemic: results from a retrospective multicenter analysis. BMC Cancer, 2025, 25(1): 91.
13. Egg M, Kietzmann T. Little strokes fell big oaks: the use of weak magnetic fields and reactive oxygen species to fight cancer. Redox Biol, 2025, 79: 103483.
14. Garcia-Estevez L, Moreno-Bueno G. Updating the role of obesity and cholesterol in breast cancer. Breast Cancer Res, 2019, 21(1): 35.
15. Kamat MA, Blackshaw JA, Young R, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics, 2019, 35(22): 4851-4853.
16. Verbanck M, Chen CY, Neale B, et al. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet, 2018, 50(5): 693-698.
17. 陈洁, 彭榆富. 乳腺癌的免疫治疗进展. 中国普外基础与临床杂志, 2019, 26(12): 1403-1408.
18. 许晶晶, 刘峰, 杨廷桐, 等. 乳腺浸润性导管癌微环境中的CD4⁺T细胞比例、CD8⁺T细胞比例及p53基因的表达. 中国普外基础与临床杂志, 2018, 25(3): 328-333.
19. Wang Z, Yang X, Shen J, et al. Gene expression patterns associated with tumor-infiltrating CD4⁺ and CD8⁺ T cells in invasive breast carcinomas. Hum Immunol, 2021, 82(4): 279-287.
20. Zahran AM, Rayan A, Zahran ZAM, et al. Overexpression of PD-1 and CD39 in tumor-infiltrating lymphocytes compared with peripheral blood lymphocytes in triple-negative breast cancer. PLoS One, 2022, 17(1): e0262650.
21. Tower H, Dall G, Davey A, et al. Estrogen-induced immune changes within the normal mammary gland. Sci Rep, 2022, 12(1): 18986.
22. Zhang H, Li Y, Liu YW, et al. Predictive value of lymphocyte subsets and lymphocyte-to-monocyte ratio in assessing the efficacy of neoadjuvant therapy in breast cancer. Sci Rep, 2024, 14(1): 12799.
23. Sirhan Z, Thyagarajan A, Sahu RP. The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer. Mil Med Res, 2022, 9(1): 39.
24. Hu XE, Yang P, Chen S, et al. Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low. Breast Cancer Res, 2023, 25(1): 34.
25. Ahuja S, Khan AA, Zaheer S. Understanding the spectrum of HER2 status in breast cancer: from HER2-positive to ultra-low HER2. Pathol Res Pract, 2024, 262: 155550.
26. Kortekaas KE, Santegoets SJ, Sturm G, et al. CD39 identifies the CD4⁺ tumor-specific T-cell population in human cancer. Cancer Immunol Res, 2020, 8(10): 1311-1321.

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