Functional annotation of breast cancer risk loci implicates perturbation of FILIP1L expression in mammary fibroblasts in influencing breast cancer risk.
Zvereva, A.; Kemp, H.; Gillespie, A.; Tomczyk, K.; Romualdo Cardoso, S.; Sevgi, S.; Mackie, K.; Fedele, V.; Alexander, J.; Goulding, I.; Gomm, J.; Jones, J. L.; Baxter, J. S.; Pettitt, S. J.; Lord, C. J.; Fletcher, O.; Haider, S.; Johnson, N.
Show abstract
Genome-wide association studies have led to the identification of more than 150 genomic regions that are associated with breast cancer risk. Translating these findings into a greater understanding of that risk requires identification of functional variants and target genes. Breast cancer progression and metastasis does not depend solely on cancer cell-autonomous defects; the stroma, of which fibroblasts comprise a dominant component, also has a functional role. We generated promoter capture Hi-C data in primary and immortalized mammary fibroblasts and identified 28 interaction peaks involving 116 credible causal breast cancer variants and 26 target genes that were exclusive to fibroblasts. Integrating these data with H3K27ac CUT&Tag peaks identified a potentially functional variant (rs17393059) and target gene (filamin A interacting protein 1 like (FILIP1L)) at the 3q12.1 breast cancer risk locus. Using genome-wide functional data in breast-relevant cell types we demonstrate that perturbation of gene expression in mammary fibroblasts may impact risk of breast cancer by a cell non-autonomous mechanism.
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