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Epidemiology

Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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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Fig. 1: The flowchart of the current study.
Fig. 2: Heatmaps of MR estimates of proteins significantly associated with risk of one or more breast cancer subtypes.
Fig. 3: Scatter plots of MR associations of TXNDC12, PLA2R1 and ICAM1 with risk of five breast cancer intrinsic-like subtypes.

Data availability

All data used in this study are publicly available summary-level data, with the relevant studies cited.

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Acknowledgements

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.

Funding

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.

Author information

Authors and Affiliations

Authors

Contributions

XS (Xiang Shu) designed the study. QZ performed the statistical analyses. XS (Xiaohui Sun) created the figures. XS (Xiang Shu) drafted the manuscript. XS (Xiang Shu), MF, XG, JL, MER, X-OS, WZ and JLB interpreted the data and edited the manuscript. All authors have given final approval of the version to be published.

Corresponding author

Correspondence to Xiang Shu.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All included datasets were approved by respective ethics/institutional review committees, in accordance with the Declaration of Helsinki.

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Supplementary information

The top 20 enriched pathways among 1890 tested proteins from overrepresentation test

41416_2022_1923_MOESM2_ESM.pdf

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

41416_2022_1923_MOESM3_ESM.pdf

Significant associations with risk of breast cancer subtypes (not previously reported for risk of overall breast cancer): full results from five MR approaches.

Bidirectional MR analysis for the identified proteins in the main analysis: from breast cancer subtype to proteins.

41416_2022_1923_MOESM5_ESM.pdf

The pQTL of eight proteins showed a moderate linkage disequilibrium (LD) with previously identified breast cancer variants

Supplementary Figures

Reporting Summary

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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

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  • DOI: https://doi.org/10.1038/s41416-022-01923-2

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