Integration of TWAS with single-cell and spatial transcriptomics identifies TLR1 as a susceptibility gene and...

Breast cancer is a common malignant tumor with a complex pathogenesis, and while genome-wide association studies (GWAS) have identified multiple risk loci, they often fall short in pinpointing specific functional susceptibility genes. To address this, we collected whole-tissue eQTL data from the GTEx portal and breast cancer GWAS summary data from the Breast Cancer Association Consortium (BCAC) and FinnGen R10 database, employing transcriptome-wide association studies (TWAS) to screen and identify susceptibility genes. Subsequently, spatial transcriptomic sequencing and single-cell RNA sequencing were employed to investigate the underlying mechanisms of these genes within the tumor microenvironment (TME) and their relevance as therapeutic targets. We identified five susceptibility genes-ADCY3, CASP8, GRHL1, HELQ, and TLR1-which are enriched in tumor-related signaling pathways such as Kras and TNFα. In the breast cancer TME, these genes are associated with myofibroblasts, mast cells, and M2 macrophages, and these cells may interact via biological pathways involving macrophage migration inhibitory factor (MIF) and secreted phosphoprotein 1 (SPP1). Notably, TLR1 may serve as a drug target, with compounds such as Doxorubicin and Etoposide identified as potential candidates. In conclusion, ADCY3, CASP8, GRHL1, HELQ, and TLR1, as genetic susceptibility genes for breast cancer, hold significant value in understanding tumor development and advancing therapy.