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

Abstract

Purpose Inherited variants in the cancer susceptibility genes, BRCA1 and BRCA2 account for up to 5% of breast cancers. Multiple gene expression studies have analysed gene expression patterns that maybe associated with BRCA12 pathogenic variant status; however, results from these studies lack consensus. These studies have focused on the differences in population means to identified genes associated with BRCA1/2-carriers with little consideration for gene expression variability, which is also under genetic control and is a feature of cellular function. Methods We measured differential gene expression variability in three of the largest familial breast cancer datasets and a 2116 breast cancer meta-cohort. Additionally, we used RNA in situ hybridisation to confirm expression variability of EN1 in an independent cohort of more than 500 breast tumours. Results BRCA1-associated breast tumours exhibited a 22.8% (95% CI 22.3–23.2) increase in transcriptome-wide gene expression variability compared to BRCAx tumours. Additionally, 40 genes were associated with BRCA1-related breast cancers that had ChIP-seq data suggestive of enriched EZH2 binding. Of these, two genes (EN1 and IGF2BP3) were significantly variable in both BRCA1-associated and basal-like breast tumours. RNA in situ analysis of EN1 supported a significant (p = 6.3 × 10−04) increase in expression variability in BRCA1-associated breast tumours. Conclusion Our novel results describe a state of increased gene expression variability in BRCA1-related and basal-like breast tumours. Furthermore, genes with increased variability may be driven by changes in DNA occupancy of epigenetic effectors. The variation in gene expression is replicable and led to the identification of novel associations between genes and disease phenotypes.

Engrailed‐1 Promotes Pancreatic Cancer Metastasis

“…EN1 has been shown to be a pro‐survival factor in brain development and associated with poor prognosis in multiple cancer types, such as adenoid cystic sarcoma, triple negative breast cancer (TNBC), nasopharyngeal carcinoma and osteosarcoma. [ 17–23 ] Our data showed that EN1 perturbations altered the expression of a number of genes involved in apoptosis‐, MYC‐, hypoxia‐ and E2F‐related pathways. For instance, we found that EN1 depletion altered MAPK pathways likely through the up‐regulation of the negative regulators such as DUSP1, promoting cell survival.…”

“…[12][13][14][15][16] In addition, several studies have reported aberrantly expressed EN1 and the association with poor prognosis in human malignancies, including glioblastoma, salivary gland adenoid cystic carcinoma, and breast-related cancers. [17][18][19][20][21][22][23] However, the detailed molecular mechanisms by which EN1 promotes PDA progression remain unknown.…”