Cross-tissue transcriptome association study identifies breast cancer susceptibility genes

Abstract

Breast cancer (BC) is a common malignant tumor of the female reproductive system, with increasing incidence and mortality rates globally, which severely threatens women’s health. Although genetic factors have been confirmed to contribute to BC development, the specific pathogenic genes and their underlying molecular mechanisms remain poorly understood. Single-tissue and cross-tissue transcriptome-wide association studies (TWAS) were performed using data from FinnGen R10 (139274 individuals: 76192 cases, 63082 controls) and GTEx v8 expression quantitative trait locus (eQTL) data, with validation conducted using functional summary-based imputation (FUSION). Susceptibility genes were screened via multi-marker analysis of genomic annotation (MAGMA) and fine-mapping of causal gene sets (FOCUS). Core risk genes were identified through Mendelian randomization (MR) and colocalization analysis. Cross-tissue TWAS identified 18 BC susceptibility genes, which were further refined to 7 candidate genes through single-tissue TWAS and MAGMA analysis. CASP8 was confirmed as the core pathogenic gene. This study establishes an association between predicted CASP8 expression and BC risk, providing novel insights into the pathogenesis of BC. Through integrative genomic analyses, this study identifies CASP8 as a key susceptibility gene for BC. A major limitation of this study is its reliance on public datasets. Further in vitro and in vivo experiments are required to verify the biological activity and molecular mechanisms of CASP8, which may facilitate the development of novel strategies for BC diagnosis and treatment.