Recurrent and functional regulatory mutations in breast cancer
Esther Rheinbay1,2, Prasanna Parasuraman2, Jonna Grimsby1
1The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02124, USA.
Abstract:
Genomic analysis of tumours has led to the identification of hundreds of cancer genes on the basis of the presence of mutations in protein-coding regions. By contrast, much less is known about cancer-causing mutations in non-coding regions. Here we perform deep sequencing in 360 primary breast cancers and develop computational methods to identify significantly mutated promoters. Clear signals are found in the promoters of three genes. FOXA1, a known driver of hormone-receptor positive breast cancer, harbours a mutational hotspot in its promoter leading to overexpression through increased E2F binding. RMRP and NEAT1, two non-coding RNA genes, carry mutations that affect protein binding to their promoters and alter expression levels. Our study shows that promoter regions harbour recurrent mutations in cancer with functional consequences and that the mutations occur at similar frequencies as in coding regions. Power analyses indicate that more such regions remain to be discovered through deep sequencing of adequately sized cohorts of patients.
Insights
Cancer-causing mutations frequently occur in promoter regions, not just coding genes. This study identified key promoter mutations in breast cancer, impacting gene expression and revealing new avenues for cancer research.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Genomic analysis has primarily focused on coding regions for cancer gene identification.
- Non-coding regions, particularly promoters, are understudied for their role in cancer development.
Purpose of the Study:
- To identify significantly mutated promoter regions in breast cancer using deep sequencing.
- To investigate the functional consequences of these promoter mutations on gene expression.
Main Methods:
- Deep sequencing of 360 primary breast cancer samples.
- Development of computational methods to detect significantly mutated promoters.
- Analysis of mutation impact on transcription factor binding and gene expression.
Main Results:
- Identified recurrent mutations in the promoters of three genes: FOXA1, RMRP, and NEAT1.
- FOXA1 promoter mutations lead to overexpression via increased E2F binding in hormone-receptor positive breast cancer.
- Mutations in RMRP and NEAT1 promoters alter protein binding and gene expression levels.
Conclusions:
- Promoter regions harbor recurrent, functionally significant mutations in cancer at frequencies comparable to coding regions.
- These findings highlight the importance of non-coding regions in cancer genomics.
- Further deep sequencing of large patient cohorts is needed to discover additional cancer-associated promoter mutations.
Related Concept Videos
02:21Cancers Originate from Somatic Mutations in a Single Cell
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
01:33Cancer-Critical Genes I: Proto-oncogenes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...