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Published on: September 25, 2018
Significance of duon mutations in cancer genomes
Vinod Kumar Yadav1,2, Kyle S Smith1,3, Colin Flinders4
1Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Abstract:
Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases. This class of mutations, recently dubbed "duon mutations" due to their dual roles, can potentially have major impacts on downstream pathways. However their significance in diseases such as cancer remain unclear. In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations. Several such mutations are detected in known cancer genes in multiple cancer types. For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways. Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways. Our findings emphasize the need to interrogate the mutations in coding regions beyond their obvious effects on protein structures.
Insights
Researchers identified "duon mutations" in cancer, which affect both protein function and gene expression. These dual-role mutations in genes like TP53 and SF3B1 may significantly impact cancer pathways.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Functional mutations impact protein structure/function and can alter gene expression.
- These dual-role mutations, termed "duon mutations," have unclear significance in cancer.
- Understanding these mutations is crucial for cancer research.
Purpose of the Study:
- To investigate the significance of duon mutations in various cancer types.
- To identify potential duon mutations and their impact on cancer pathways.
- To highlight the importance of considering dual roles of mutations.
Main Methods:
- Analyzed 4606 samples across 19 cancer types.
- Integrated allelic expression, mRNA expression, regulatory motif perturbation, and chromatin signatures.
- Developed a composite index, the REDACT score, to identify potential duon mutations.
Main Results:
- Identified several potential duon mutations in known cancer genes across multiple cancer types.
- Observed a duon mutation in TP53 associated with increased mutant allelic expression.
- Found a duon mutation in SF3B1 linked to abnormal splicing and altered angiogenesis/matrix degradation pathways.
Conclusions:
- Duon mutations play a significant role in cancer, affecting both protein function and gene expression.
- These findings necessitate a broader interrogation of coding region mutations beyond protein structure.
- Further research into duon mutations can uncover new therapeutic targets and strategies in oncology.
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