The aetiologic role of circulating proteins in the development of breast cancer subtypes is not clear. We aimed to examine the potential causal effects of circulating proteins on the risk of breast cancer by intrinsic-like subtypes within the Mendelian randomisation (MR) framework.
MR was performed using summary statistics from two sources: the INTERVAL protein quantitative trait loci (pQTL) Study (1890 circulating proteins and 3301 healthy individuals) and the Breast Cancer Association Consortium (BCAC; 106,278 invasive cases and 91,477 controls). The inverse-variance (IVW)-weighted method was used as the main analysis to evaluate the associations between genetically predicted proteins and the risk of five different intrinsic-like breast cancer subtypes and the weighted median MR method, the Egger regression, the MR-PRESSO, and the MRLocus method were performed as secondary analysis.
We identified 98 unique proteins significantly associated with the risk of one or more subtypes (Benjamini–Hochberg false discovery rate < 0.05). Among them, 51 were potentially specific to luminal A-like subtype, 14 to luminal B/Her2-negative-like, 11 to triple negative, 3 to luminal B-like, and 2 to Her2-enriched-like breast cancer (ntotal = 81). Associations for three proteins (ICAM1, PLA2R1 and TXNDC12) showed evident heterogeneity across the subtypes. For example, higher levels of genetically predicted ICAM1 (per unit of increase) were associated with an increased risk of luminal B/HER2-negative-like cancer (OR = 1.06, 95% CI = 1.03–1.08, BH-FDR = 2.43 × 10−4) while inversely associated with triple-negative breast cancer with borderline significance (OR = 0.97, 95% CI = 0.95–0.99, BH-FDR = 0.065, Pheterogeneity < 0.005).
Our study found potential causal associations with the risk of subtypes of breast cancer for 98 proteins. Associations of ICAM1, PLA2R1 and TXNDC12 varied substantially across the subtypes. The identified proteins may partly explain the heterogeneity in the aetiology of distinct subtypes of breast cancer and facilitate the personalised risk assessment of the malignancy.
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The authors would like to thank the researchers of the Breast Cancer Association Consortium (BCAC), as well as Benjamin B Sun and colleagues for sharing summary statistics of GWAS.
XS (Xiang Shu) is supported, in part, by R00CA230205; XS (Xiaohui Sun) is supported by R00CA230205 & China Scholarship Council (CSC) (202108330197); MF is supported by the Quantitative Sciences Undergraduate Research Experience through R25CA214255; WZ is supported, in part by R01CA202981 and R01CA235553 for breast cancer research. We also acknowledge the Memorial Sloan Kettering P30 Cancer Center Support Grant (P30CA008748) for the statistical support.
The authors declare no competing interests.
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Previously reported proteins, comparisons between the associations with risk of overall breast cancer and associations with risk of breast cancer subtypes: Full results from five MR approaches
Significant associations with risk of breast cancer subtypes (not previously reported for risk of overall breast cancer): full results from five MR approaches.
The pQTL of eight proteins showed a moderate linkage disequilibrium (LD) with previously identified breast cancer variants
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Shu, X., Zhou, Q., Sun, X. et al. Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-01923-2