Multi-Ancestry Transcriptome-wide Association Studies Uncover New Insights into Breast Cancer Genetics and Biology.

Area of Science:

• Genetics
• Genomics
• Cancer Biology

Background:

• Genome-wide association studies (GWAS) have identified numerous breast cancer genetic risk loci, but the specific target genes are often unknown.
• A significant knowledge gap exists in understanding the functional genetic basis of breast cancer susceptibility.

Purpose of the Study:

• To discover novel breast cancer susceptibility genes using multi-ancestry transcriptome-wide association studies (TWAS).
• To identify genes associated with breast cancer risk, including those independent of known risk variants and those with differential effects based on estrogen receptor status.

Main Methods:

• Developed and validated ancestry-specific genetic models for gene expression, splicing, and polyadenylation using normal breast tissue data from 652 females.
• Applied these models to large-scale GWAS data (178,534 cases, 248,300 controls) for association analyses.
• Utilized single-cell RNA sequencing and in vitro experiments for functional validation.

Main Results:

• Identified 290 genes associated with breast cancer risk, with 103 being novel TWAS findings and 46 located far from known risk variants.
• Discovered 39 genes with distinct associations based on estrogen receptor status.
• Found enrichment in key pathways including homologous recombination, apoptosis, p53, PI3K/AKT/mTOR, estrogen, and IL-2/STAT5 signaling. Functional evidence supported 169 genes.

Conclusions:

• Uncovered a substantial number of candidate breast cancer susceptibility genes, significantly advancing the understanding of its genetic architecture.
• Provided valuable insights into the molecular mechanisms underlying breast cancer development and progression.
• Highlighted the importance of multi-ancestry TWAS in gene discovery for complex diseases.