Causal associations between immune cell phenotypes and <i>HER</i> 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 cell phenotypes 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 using immune cell phenotype and breast cancer were used with inverse variance weighting as the primary analytical method; horizontal pleiotropy was tested using MR-PRESSO and outliers were corrected; in addition, the reliability of the obtained data was verified using Cochran’s Q test, Mendelian randomization (MR)- Egger regression and leave-one-out method were used to verify the reliability of the obtained data. Results For HER⁺ breast cancer, CD3 on CD39⁺CD4⁺T cell [ OR=0.940, 95%CI (0.913, 0.968), P=0.019] was protective factor. 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 [OR=0.951, 95%CI (0.930, 0.973), P=0.014], CD3 on secreting CD4 regulatory T cell [OR=0.949, 95%CI (0.925, 0.974), P=0.023] were protective factors. Conclusion There is a causal association between certain immune cell phenotypes and breast cancer, which may be predictive markers for early diagnosis of breast cancer and development of new immunotherapies.

Citation： LIU Wenyan, DU Kaihao, WANG Wei, MA Zhijun. 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, 2025, 32(8): 959-963. doi: 10.7507/1007-9424.202412015 Copy

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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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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. doi: 10.1371/journal.pone.0262650.
21.	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. doi: doi: 10.1186/s40779-022-00401-3.
22.	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. doi: 10.1186/s13058-023-01639-y.
23.	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. doi: 10.1016/j.prp.2024.155550.
24.	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. doi: 10.3390/cells10020223.
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. doi: 10.1186/s12888-023-05081-4.
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. doi: 10.3390/ijerph18126409.
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. doi: 10.1186/s12885-025-13425-4.
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. doi: 10.1016/j.redox.2024.103483.
14. Garcia-Estevez L, Moreno-Bueno G. Updating the role of obesity and cholesterol in breast cancer. Breast Cancer Res, 2019, 21(1): 35. doi: 10.1186/s13058-019-1124-1.
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. doi: 10.1371/journal.pone.0262650.
21. 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. doi: doi: 10.1186/s40779-022-00401-3.
22. 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. doi: 10.1186/s13058-023-01639-y.
23. 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. doi: 10.1016/j.prp.2024.155550.
24. 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.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Causal associations between immune cell phenotypes and HER genes of breast cancer based on Mendelian randomization

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