Causal association between thyroid nodules and breast neoplasms: a bidirectional two-sample Mendelian randomization study_Chinese Journal of Evidence-Based Medicine

Authors：

LI Junyi ¹ , LI Shixin ² , SONG Aolin ³ , ZHANG Dongpo ¹ , ZHU Yibing ¹ , XING Xiaoxiao ¹ , MO Juefei ¹ , LIAO Daixiang ¹ ,  LI Jie ¹

1. Surgical department, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P. R. China;
2. Department of Oncology, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550025, P. R. China;
3. Department of Dermatology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P. R. China;

Corresponding author：

LI Jie, Email: qfm2020jieli@yeah.net

Keywords：

Thyroid diseases; Malignant neoplasm of breast; Benign neoplasm of breast; Mendelian randomization; Causal relationship

DOI：

10.7507/1672-2531.202502117

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective Thyroid nodules are an exceptionally common thyroid disorder. Past studies suggested a possible link between thyroid diseases and breast neoplasms. However, few studies have delved into the causal relationship between thyroid nodules and breast neoplasms. This study conducted a Mendelian randomization (MR) analysis to further investigate the causal relationship between them. Methods This study was conducted using data sourced from genome-wide association study (GWAS) summary datasets. The study focused on thyroid nodules, benign breast tumors, and malignant breast cancers as the research objects, and relevant single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs). The inverse-variance weighted (IVW) was primarily used to assess the causal relationship between thyroid nodules and breast neoplasms. Cochran’s Q test was employed to detect heterogeneity, while MR-Egger intercept and MR-PRESSO were used to test for pleiotropy. Sensitivity analysis was conducted using the leave-one-out method. Results There was a significant causal relationship between thyroid nodules and malignant neoplasm of breast (OR=0.88, 95%CI 0.83 to 0.95, P<0.01), with no evidence of reverse causality between them (OR=1.01, 95%CI 0.99 to 1.03, P=0.16). No causal relationship was found between thyroid nodules and benign neoplasm of breast, as indicated by both forward MR analysis (OR=0.97, 95%CI 0.89 to 1.06, P=0.51) and reverse MR analysis (OR=0.97, 95%CI 0.92 to 1.04, P=0.40). Sensitivity analyses suggested that the study findings were accurate and reliable. Conclusion The present study identifies thyroid nodules as a potential protective factor for malignant neoplasm of breast.

1.	Pradeep Prabhu P, Mohanty B, Lobo CL, et al. Harnessing the nutriceutics in early-stage breast cancer: mechanisms, combinational therapy, and drug delivery. J Nanobiotechnology, 2024, 22(1): 574.
2.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3.	World Health Organization. Global cancer observatory (GcO): cancer today. 2020.
4.	Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Trans Med Chir Soc Edinb. 1896, 15: 153-179.
5.	Gago-Dominguez M, Castelao JE. Role of lipid peroxidation and oxidative stress in the association between thyroid diseases and breast cancer. Crit Rev Oncol Hematol, 2008, 68(2): 107-114.
6.	Smyth PP. The thyroid and breast cancer. Curr Opin Endocrinol Diabetes Obes, 2016, 23(5): 389-393.
7.	Garner CN, Ganetzky R, Brainard J, et al. Increased prevalence of breast cancer among patients with thyroid and parathyroid disease. Surgery, 2007, 142(6): 806-813.
8.	Van Fossen VL, Wilhelm SM, Eaton JL, et al. Association of thyroid, breast and renal cell cancer: a population-based study of the prevalence of second malignancies. Ann Surg Oncol, 2013, 20(4): 1341-1347.
9.	Smyth PP. The thyroid and breast cancer: a significant association. Ann Med, 1997, 29(3): 189-191.
10.	Chung WY, Chang HS, Kim EK, et al. Ultrasonographic mass screening for thyroid carcinoma: a study in women scheduled to undergo a breast examination. Surg Today, 2001, 31(9): 763-767.
11.	Ma CY, Liang XY, Ran L, et al. Prevalence and risk factors of thyroid nodules in breast cancer women with different clinicopathological characteristics: a cross-sectional study. Clin Transl Oncol, 2024, 26(9): 2380-2387.
12.	Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 2016, 26(1): 1-133.
13.	Matti B, Cohen-Hallaleh R. Overview of the 2015 American Thyroid Association guidelines for managing thyroid nodules and differentiated thyroid cancer. N Z Med J. 2016, 129(1441): 78-86.
14.	Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab, 1955, 15(10): 1270-1280.
15.	Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16.	Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-98.
17.	Yao S, Zhang M, Dong SS, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav, 2022, 6(11): 1569-1576.
18.	王丽娜, 张真. 孟德尔随机化方法在因果推断中的应用. 中华流行病学杂志, 2017, 38(4): 547-552.
19.	Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
20.	Huang W, Xiao J, Ji J, et al. Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study. Elife, 2021, 10: e73873.
21.	Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
22.	Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
23.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
24.	Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
25.	Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
26.	Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
27.	Chen J, Yuan S, Fu T, et al. Gastrointestinal consequences of type 2 diabetes mellitus and impaired glycemic homeostasis: a Mendelian randomization study. Diabetes Care, 2023, 46(4): 828-835.
28.	Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
29.	McVicker L, Cardwell CR, McIntosh SA, et al. Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study. Breast Cancer Res Treat, 2022, 195(2): 209-221.
30.	Peixoto MS, de Vasconcelos E Souza A, Andrade IS, et al. Hypothyroidism induces oxidative stress and DNA damage in breast. Endocr Relat Cancer, 2021, 28(7): 505-519.
31.	Huang CH, Wei JC, Chien TC, et al. Risk of breast cancer in females with hypothyroidism: a nationwide, population-based, cohort study. Endocr Pract, 2021, 27(4): 298-305.
32.	Mittra I, Hayward JL, McNeilly AS. Hypothalamic-pituitary-prolactin axis in breast cancer. Lancet, 1974, 1(7863): 889-891.
33.	Smyth PP, Smith DF, McDermott EW, et al. A direct relationship between thyroid enlargement and breast cancer. J Clin Endocrinol Metab, 1996, 81(3): 937-941.
34.	Tran TV, Kitahara CM, Leenhardt L, et al. The effect of thyroid dysfunction on breast cancer risk: an updated meta-analysis. Endocr Relat Cancer, 2022, 30(1): e220155.
35.	Campennì A, Avram AM, Verburg FA, et al. The EANM guideline on radioiodine therapy of benign thyroid disease. Eur J Nucl Med Mol Imaging, 2023, 50(11): 3324-3348.
36.	Han M, Wang Y, Jin Y, et al. Benign thyroid disease and the risk of breast cancer: an updated systematic review and meta-analysis. Front Endocrinol (Lausanne), 2022, 13: 984593.
37.	Sarlis NJ, Gourgiotis L, Pucino F, et al. Lack of association between Hashimoto thyroiditis and breast cancer: a quantitative research synthesis. Hormones (Athens), 2002, 1(1): 35-41.
38.	Turken O, NarIn Y, DemIrbas S, et al. Breast cancer in association with thyroid disorders. Breast Cancer Res, 2003, 5(5): R110-113.
39.	Smyth PP, Shering SG, Kilbane MT, et al. Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma. J Clin Endocrinol Metab, 1998, 83(8): 2711-2716.
40.	Park JW, Zhao L, Willingham M, et al. Oncogenic mutations of thyroid hormone receptor β. Oncotarget, 2015, 6(10): 8115-8131.
41.	Rebaï M, Kallel I, Hamza F, et al. Association of EGFR and HER2 polymorphisms with risk and clinical features of thyroid cancer. Genet Test Mol Biomarkers, 2009, 13(6): 779-784.
42.	Dinda S, Sanchez A, Moudgil V. Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Oncogene, 2002, 21(5): 761-768.
43.	Hall LC, Salazar EP, Kane SR, et al. Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol, 2008, 109(1-2): 57-66.
44.	Dong L, Lu J, Zhao B, et al. Review of the possible association between thyroid and breast carcinoma. World J Surg Oncol, 2018, 16(1): 130.
45.	Hardefeldt PJ, Eslick GD, Edirimanne S. Benign thyroid disease is associated with breast cancer: a meta-analysis. Breast Cancer Res Treat, 2012, 133(3): 1169-1177.
46.	García-Silva S, Aranda A. The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol Cell Biol, 2004, 24(17): 7514-7523.
47.	Conde I, Paniagua R, Zamora J, et al. Influence of thyroid hormone receptors on breast cancer cell proliferation. Ann Oncol, 2006, 17(1): 60-64.
48.	Søgaard M, Farkas DK, Ehrenstein V, et al. Hypothyroidism and hyperthyroidism and breast cancer risk: a nationwide cohort study. Eur J Endocrinol, 2016, 174(4): 409-414.
49.	Tosovic A, Becker C, Bondeson AG, et al. Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk. Int J Cancer, 2012, 131(9): 2126-2133.
50.	Pang XP, Yoshimura M, Hershman JM. Suppression of rat thyrotroph and thyroid cell function by tumor necrosis factor-alpha. Thyroid, 1993, 3(4): 325-330.
51.	Poth M, Tseng YC, Wartofsky L. Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness. Thyroid, 1991, 1(3): 235-240.
52.	Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922.
53.	Fang Y, Yao L, Sun J, et al. Does thyroid dysfunction increase the risk of breast cancer. A systematic review and meta-analysis. J Endocrinol Invest, 2017, 40(10): 1035-1047.
54.	Piccardo A, Fiz F, Bottoni G, et al. The FDG pattern of autonomously functioning thyroid nodules correlates with thyroid-stimulating hormone and histopathology. Clin Nucl Med, 2023, 48(2): 119-125.

1. Pradeep Prabhu P, Mohanty B, Lobo CL, et al. Harnessing the nutriceutics in early-stage breast cancer: mechanisms, combinational therapy, and drug delivery. J Nanobiotechnology, 2024, 22(1): 574.
2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
3. World Health Organization. Global cancer observatory (GcO): cancer today. 2020.
4. Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Trans Med Chir Soc Edinb. 1896, 15: 153-179.
5. Gago-Dominguez M, Castelao JE. Role of lipid peroxidation and oxidative stress in the association between thyroid diseases and breast cancer. Crit Rev Oncol Hematol, 2008, 68(2): 107-114.
6. Smyth PP. The thyroid and breast cancer. Curr Opin Endocrinol Diabetes Obes, 2016, 23(5): 389-393.
7. Garner CN, Ganetzky R, Brainard J, et al. Increased prevalence of breast cancer among patients with thyroid and parathyroid disease. Surgery, 2007, 142(6): 806-813.
8. Van Fossen VL, Wilhelm SM, Eaton JL, et al. Association of thyroid, breast and renal cell cancer: a population-based study of the prevalence of second malignancies. Ann Surg Oncol, 2013, 20(4): 1341-1347.
9. Smyth PP. The thyroid and breast cancer: a significant association. Ann Med, 1997, 29(3): 189-191.
10. Chung WY, Chang HS, Kim EK, et al. Ultrasonographic mass screening for thyroid carcinoma: a study in women scheduled to undergo a breast examination. Surg Today, 2001, 31(9): 763-767.
11. Ma CY, Liang XY, Ran L, et al. Prevalence and risk factors of thyroid nodules in breast cancer women with different clinicopathological characteristics: a cross-sectional study. Clin Transl Oncol, 2024, 26(9): 2380-2387.
12. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 2016, 26(1): 1-133.
13. Matti B, Cohen-Hallaleh R. Overview of the 2015 American Thyroid Association guidelines for managing thyroid nodules and differentiated thyroid cancer. N Z Med J. 2016, 129(1441): 78-86.
14. Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab, 1955, 15(10): 1270-1280.
15. Birney E. Mendelian randomization. Cold Spring Harb Perspect Med, 2022, 12(4): a041302.
16. Davey Smith G, Hemani G. Mendelian randomization: genetic anchors for causal inference in epidemiological studies. Hum Mol Genet, 2014, 23(R1): R89-98.
17. Yao S, Zhang M, Dong SS, et al. Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nat Hum Behav, 2022, 6(11): 1569-1576.
18. 王丽娜, 张真. 孟德尔随机化方法在因果推断中的应用. 中华流行病学杂志, 2017, 38(4): 547-552.
19. Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
20. Huang W, Xiao J, Ji J, et al. Association of lipid-lowering drugs with COVID-19 outcomes from a Mendelian randomization study. Elife, 2021, 10: e73873.
21. Burgess S, Thompson SG; CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol, 2011, 40(3): 755-764.
22. Burgess S, Scott RA, Timpson NJ, et al. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol, 2015, 30(7): 543-552.
23. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
24. Bowden J, Davey Smith G, Haycock PC, et al. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol, 2016, 40(4): 304-314.
25. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol, 2017, 46(6): 1985-1998.
26. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol, 2015, 44(2): 512-525.
27. Chen J, Yuan S, Fu T, et al. Gastrointestinal consequences of type 2 diabetes mellitus and impaired glycemic homeostasis: a Mendelian randomization study. Diabetes Care, 2023, 46(4): 828-835.
28. Hemani G, Zheng J, Elsworth B, et al. The MR-base platform supports systematic causal inference across the human phenome. Elife, 2018, 7: e34408.
29. McVicker L, Cardwell CR, McIntosh SA, et al. Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study. Breast Cancer Res Treat, 2022, 195(2): 209-221.
30. Peixoto MS, de Vasconcelos E Souza A, Andrade IS, et al. Hypothyroidism induces oxidative stress and DNA damage in breast. Endocr Relat Cancer, 2021, 28(7): 505-519.
31. Huang CH, Wei JC, Chien TC, et al. Risk of breast cancer in females with hypothyroidism: a nationwide, population-based, cohort study. Endocr Pract, 2021, 27(4): 298-305.
32. Mittra I, Hayward JL, McNeilly AS. Hypothalamic-pituitary-prolactin axis in breast cancer. Lancet, 1974, 1(7863): 889-891.
33. Smyth PP, Smith DF, McDermott EW, et al. A direct relationship between thyroid enlargement and breast cancer. J Clin Endocrinol Metab, 1996, 81(3): 937-941.
34. Tran TV, Kitahara CM, Leenhardt L, et al. The effect of thyroid dysfunction on breast cancer risk: an updated meta-analysis. Endocr Relat Cancer, 2022, 30(1): e220155.
35. Campennì A, Avram AM, Verburg FA, et al. The EANM guideline on radioiodine therapy of benign thyroid disease. Eur J Nucl Med Mol Imaging, 2023, 50(11): 3324-3348.
36. Han M, Wang Y, Jin Y, et al. Benign thyroid disease and the risk of breast cancer: an updated systematic review and meta-analysis. Front Endocrinol (Lausanne), 2022, 13: 984593.
37. Sarlis NJ, Gourgiotis L, Pucino F, et al. Lack of association between Hashimoto thyroiditis and breast cancer: a quantitative research synthesis. Hormones (Athens), 2002, 1(1): 35-41.
38. Turken O, NarIn Y, DemIrbas S, et al. Breast cancer in association with thyroid disorders. Breast Cancer Res, 2003, 5(5): R110-113.
39. Smyth PP, Shering SG, Kilbane MT, et al. Serum thyroid peroxidase autoantibodies, thyroid volume, and outcome in breast carcinoma. J Clin Endocrinol Metab, 1998, 83(8): 2711-2716.
40. Park JW, Zhao L, Willingham M, et al. Oncogenic mutations of thyroid hormone receptor β. Oncotarget, 2015, 6(10): 8115-8131.
41. Rebaï M, Kallel I, Hamza F, et al. Association of EGFR and HER2 polymorphisms with risk and clinical features of thyroid cancer. Genet Test Mol Biomarkers, 2009, 13(6): 779-784.
42. Dinda S, Sanchez A, Moudgil V. Estrogen-like effects of thyroid hormone on the regulation of tumor suppressor proteins, p53 and retinoblastoma, in breast cancer cells. Oncogene, 2002, 21(5): 761-768.
43. Hall LC, Salazar EP, Kane SR, et al. Effects of thyroid hormones on human breast cancer cell proliferation. J Steroid Biochem Mol Biol, 2008, 109(1-2): 57-66.
44. Dong L, Lu J, Zhao B, et al. Review of the possible association between thyroid and breast carcinoma. World J Surg Oncol, 2018, 16(1): 130.
45. Hardefeldt PJ, Eslick GD, Edirimanne S. Benign thyroid disease is associated with breast cancer: a meta-analysis. Breast Cancer Res Treat, 2012, 133(3): 1169-1177.
46. García-Silva S, Aranda A. The thyroid hormone receptor is a suppressor of ras-mediated transcription, proliferation, and transformation. Mol Cell Biol, 2004, 24(17): 7514-7523.
47. Conde I, Paniagua R, Zamora J, et al. Influence of thyroid hormone receptors on breast cancer cell proliferation. Ann Oncol, 2006, 17(1): 60-64.
48. Søgaard M, Farkas DK, Ehrenstein V, et al. Hypothyroidism and hyperthyroidism and breast cancer risk: a nationwide cohort study. Eur J Endocrinol, 2016, 174(4): 409-414.
49. Tosovic A, Becker C, Bondeson AG, et al. Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk. Int J Cancer, 2012, 131(9): 2126-2133.
50. Pang XP, Yoshimura M, Hershman JM. Suppression of rat thyrotroph and thyroid cell function by tumor necrosis factor-alpha. Thyroid, 1993, 3(4): 325-330.
51. Poth M, Tseng YC, Wartofsky L. Inhibition of TSH activation of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness. Thyroid, 1991, 1(3): 235-240.
52. Lin Z, Deng Y, Pan W. Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model. PLoS Genet, 2021, 17(11): e1009922.
53. Fang Y, Yao L, Sun J, et al. Does thyroid dysfunction increase the risk of breast cancer. A systematic review and meta-analysis. J Endocrinol Invest, 2017, 40(10): 1035-1047.
54. Piccardo A, Fiz F, Bottoni G, et al. The FDG pattern of autonomously functioning thyroid nodules correlates with thyroid-stimulating hormone and histopathology. Clin Nucl Med, 2023, 48(2): 119-125.

Chinese Journal of Evidence-Based Medicine

Latest ArticlesCausal association between thyroid nodules and breast neoplasms: a bidirectional two-sample Mendelian randomization study

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