Thyroid disease and breast cancer, benign breast neoplasm: a two-sample Mendelian randomization study

Breast cancer (BC) is a prevalent and significant health issue and a major contributor to global cancer incidence, accounting for 31% of all reported cases in women. Benign breast neoplasm, as a benign tumor with a high incidence in women, may play an important role in the development of BC. Previous studies have shown that thyroid dysfunction and thyroid cancer (TC) can lead to the occurrence of many cancers. Therefore, we conduct Mendelian randomization (MR) analysis to explore the causality of thyroid dysfunctions, TC, and breast neoplasm.

The data of the analysis from the genome-wide association study (GWAS) dataset. The exposure includes FT4, TSH, hypothyroidism, hyperthyroidism, and TC. Meanwhile, the outcome consists of BC, HER2-enriched BC, HER2-negative BC, and benign breast neoplasm. We used five methods (inverse variance weighted (IVW) random effects model, IVW fixed effects model, MR-Egger method, median weighted method, and the weighted mode method). We used the MR-PRESSO test and MR-Egger intercept test to detect horizontal pleiotropy and Cochran's Q test to detect heterogeneity.

The IVW method showed a positive relationship between high FT4 levels and BC (OR = 1.210 p = 0.008) and an inverse association between TSH levels (OR IVW = 0.908 p = 0.007), hypothyroidism (OR IVW = 0.959, p = 0.014) and BC. For HER2-positive BC, an elevated FT4 level was associated with an increased risk (OR IVW = 1.314, p = 0.001). Genetically predicted high TSH levels (OR IVW = 0.899, p = 0.02) and hypothyroidism (OR IVW = 0.944, p = 0.003) were associated with a decreased risk of HER2-positive BC. Meanwhile, individuals with TC (OR = 1.003, p = 0.048), and hyperthyroidism (OR IVW = 1.127, p = 0.006) were associated with an increasing risk of development of benign breast neoplasm. Hyperthyroidism was associated with an elevated risk of benign breast neoplasm.

The present MR study explains the association between thyroid diseases and BC (mainly in HER2-positive BC). Furthermore, it demonstrates that hyperthyroidism, low levels of TSH, and TC may contribute to the development of benign breast neoplasm.