Increased gene expression variability in BRCA1-associated and basal-like breast tumours

Area of Science:

• Genomics
• Cancer Biology
• Epigenetics

Background:

• Inherited BRCA1 and BRCA2 variants contribute to 5% of breast cancers.
• Previous gene expression studies show inconsistent results regarding BRCA1/2 pathogenic variants.
• Gene expression variability, under genetic control, is crucial for cellular function but often overlooked in BRCA1/2 studies.

Purpose of the Study:

• To investigate differential gene expression variability in BRCA1/2-associated breast cancers.
• To identify specific genes exhibiting altered expression variability linked to BRCA1 pathogenic variants.
• To explore the role of epigenetic modifications in driving gene expression variability in BRCA1-related breast cancer.

Main Methods:

• Analysis of gene expression variability in three large familial breast cancer datasets and a 2116-case meta-cohort.
• Utilized RNA in situ hybridization to validate EN1 expression variability in over 500 breast tumors.
• ChIP-seq data analysis to identify potential EZH2 binding sites in BRCA1-associated genes.

Main Results:

• BRCA1-associated breast tumors showed a 22.8% increase in transcriptome-wide gene expression variability compared to BRCAx tumors.
• Identified 40 genes associated with BRCA1-related cancers, with EN1 and IGF2BP3 showing significant variability in both BRCA1-associated and basal-like tumors.
• RNA in situ hybridization confirmed significantly increased EN1 expression variability in BRCA1-associated breast tumors (p=6.3×10⁻⁰⁴).

Conclusions:

• BRCA1-related and basal-like breast tumors exhibit increased gene expression variability.
• Epigenetic effector DNA occupancy changes may drive this observed gene expression variability.
• The findings are replicable and reveal novel associations between gene expression variability and breast cancer phenotypes.