Abstract
Here we use single-cell RNA sequencing to compile a human breast cell atlas assembled from 55 donors that had undergone reduction mammoplasties or risk reduction mastectomies. From more than 800,000 cells we identified 41 cell subclusters across the epithelial, immune and stromal compartments. The contribution of these different clusters varied according to the natural history of the tissue. Age, parity and germline mutations, known to modulate the risk of developing breast cancer, affected the homeostatic cellular state of the breast in different ways. We found that immune cells from BRCA1 or BRCA2 carriers had a distinct gene expression signature indicative of potential immune exhaustion, which was validated by immunohistochemistry. This suggests that immune-escape mechanisms could manifest in non-cancerous tissues very early during tumor initiation. This atlas is a rich resource that can be used to inform novel approaches for early detection and prevention of breast cancer.
| Original language | English |
|---|---|
| Pages (from-to) | 652-662 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 56 |
| Issue number | 4 |
| Early online date | 28 Mar 2024 |
| DOIs | |
| Publication status | Published - Apr 2024 |
Bibliographical note
A.D.R. performed the majority of the bioinformatic analysis and interpretation of the data. S.P. contributed to the study design, sample processing, analysis and interpretation of the data. J.S. contributed to the sample processing. D.J.K. and P.H. contributed to the data processing, batch correction and cell cluster identification. A.S. contributed to the design of the sample batches and contributed to the analysis of the raw data. A.J.T. contributed to the analysis of the data and Figure design. L.J.P. performed the immune histochemistry validations. K.H. assisted A.D.R. with the inferCNV analysis and interpretation. P.H. assisted with the subclustering of immune cells and scVI integration analysis. A.Q.S. performed the immunofluorescence quantification. K.K. performed all the scRNA-seq library preparation and sequencing. R.B.M., I.G., J.J.G., V.S. and J.L.J. provided the human tissues and the metadata from the 55 donors. A.D.R., S.P., J.C.M. and W.T.K. wrote the paper. J.C.M. and W.T.K. conceptualized and supervised the study.Data Availability Statement
The authors declare that all data supporting the findings of this study and unprocessed images are available within the article and its supplementary information. The raw sequencing data and CellRanger raw outputs are available on ArrayExpress with accession number E-MTAB-13664. Processed data from our study, as well as the iHBCA, can be found and explored using the user-friendly CELLxGENE at https://cellxgene.cziscience.com/collections/48259aa8-f168-4bf5-b797-af8e88da6637. The trained CellTypist logistic regression models for label transfer can be downloaded from https://doi.org/10.5281/zenodo.10044650 (ref. 52).Code availability
All code is available on GitHub at https://github.com/MarioniLab/hbca (ref. 53).
Keywords
- Adult
- BRCA1 Protein/genetics
- BRCA2 Protein/genetics
- Breast Neoplasms/genetics
- Female
- Genes, BRCA2
- Germ-Line Mutation
- Humans
- Pregnancy
Access to Document
- Reed_etal_NG_A_Single_Cell_VOR
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