Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: A Mendelian randomisation analysis Journal Article
| Authors: | Shu, X.; Zhou, Q.; Sun, X.; Flesaker, M.; Guo, X.; Long, J.; Robson, M. E.; Shu, X. O.; Zheng, W.; Bernstein, J. L. |
| Article Title: | 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. © 2022, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | genetics; metabolism; pathology; breast neoplasms; tumor marker; breast tumor; triple negative breast cancer; mendelian randomization analysis; humans; human; female; biomarkers, tumor; triple negative breast neoplasms; phospholipase a2 receptor; pla2r1 protein, human; protein disulfide reductase (glutathione); txndc12 protein, human; receptors, phospholipase a2 |
| Journal Title: | British Journal of Cancer |
| Volume: | 127 |
| Issue: | 8 |
| ISSN: | 0007-0920 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-11-01 |
| Start Page: | 1507 |
| End Page: | 1514 |
| Language: | English |
| DOI: | 10.1038/s41416-022-01923-2 |
| PUBMED: | 35882941 |
| PROVIDER: | scopus |
| PMCID: | PMC9553869 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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