Genome-wide analysis of noncoding regulatory mutations in cancer
Nils Weinhold1, Anders Jacobsen2, Nikolaus Schultz1
1Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Abstract:
Cancer primarily develops because of somatic alterations in the genome. Advances in sequencing have enabled large-scale sequencing studies across many tumor types, emphasizing the discovery of alterations in protein-coding genes. However, the protein-coding exome comprises less than 2% of the human genome. Here we analyze the complete genome sequences of 863 human tumors from The Cancer Genome Atlas and other sources to systematically identify noncoding regions that are recurrently mutated in cancer. We use new frequency- and sequence-based approaches to comprehensively scan the genome for noncoding mutations with potential regulatory impact. These methods identify recurrent mutations in regulatory elements upstream of PLEKHS1, WDR74 and SDHD, as well as previously identified mutations in the TERT promoter. SDHD promoter mutations are frequent in melanoma and are associated with reduced gene expression and poor prognosis. The non-protein-coding cancer genome remains widely unexplored, and our findings represent a step toward targeting the entire genome for clinical purposes.
Insights
Scientists analyzed 863 tumor genomes to find noncoding mutations in cancer. They identified new mutations in regulatory elements, revealing a largely unexplored area of the cancer genome with clinical potential.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Cancer arises from somatic genomic alterations, with a focus on protein-coding genes.
- The protein-coding exome represents less than 2% of the human genome, leaving noncoding regions largely unexplored.
- Large-scale sequencing studies have advanced cancer genomics but primarily target coding regions.
Purpose of the Study:
- To systematically identify recurrently mutated noncoding regions in cancer genomes.
- To discover noncoding mutations with potential regulatory impact across the entire genome.
- To explore the clinical relevance of noncoding mutations in cancer.
Main Methods:
- Analysis of complete genome sequences from 863 human tumors (The Cancer Genome Atlas and other sources).
- Application of novel frequency- and sequence-based approaches to scan the genome for noncoding mutations.
- Identification of mutations in regulatory elements and assessment of their impact on gene expression and prognosis.
Main Results:
- Recurrent mutations were identified in regulatory elements upstream of PLEKHS1, WDR74, and SDHD.
- Previously identified TERT promoter mutations were confirmed.
- SDHD promoter mutations, frequent in melanoma, were associated with reduced gene expression and poor prognosis.
Conclusions:
- The non-protein-coding cancer genome is a significant and largely unexplored reservoir of cancer-driving mutations.
- Recurrent noncoding mutations can have regulatory functions and impact clinical outcomes.
- These findings represent a step towards a comprehensive, whole-genome approach to cancer research and clinical applications.
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