Functional Screenings Identify Regulatory Variants Associated with Breast Cancer Susceptibility

Area of Science:

• Genomics
• Cancer Biology
• Molecular Genetics

Background:

• Genome-wide association studies (GWAS) have identified numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs), primarily in non-coding regions.
• The functional roles of these non-coding SNPs as gene regulatory elements remain largely uncharacterized.
• Understanding these regulatory SNPs is crucial for accurate breast cancer risk prediction and therapeutic targeting.

Purpose of the Study:

• To identify functional single nucleotide polymorphisms (SNPs) associated with breast cancer risk.
• To elucidate the mechanisms by which these SNPs influence gene expression and cancer progression.
• To nominate candidate genes and regulatory elements involved in breast cancer pathogenesis.

Main Methods:

• Application of Dinucleotide Parallel Reporter sequencing (DiR-seq) to assess 288 breast cancer risk SNPs.
• Integration of multi-omics data, including ATAC-seq, DNase-seq, and ChIP-seq, in nine breast cancer cell lines.
• Functional investigations to determine the impact of specific SNPs on gene expression and cellular processes.

Main Results:

• Seven functional breast cancer risk SNPs were nominated through multi-omics analysis.
• The SNP rs4808611 was found to influence breast cancer progression by altering NR2F6 gene expression.
• The SNP rs2236007 affects PAX9 expression by modulating transcription factor EGR1 binding, correlating with poor patient prognosis.

Conclusions:

• This research defines functional risk SNPs and their associated genes, enhancing our understanding of breast cancer etiology.
• The identified SNPs and their regulatory mechanisms provide potential targets for breast cancer risk prediction and intervention.
• The study highlights the importance of investigating non-coding variants for a comprehensive view of cancer genetics.