INTERNATIONAL CONGRESS OF
CancerGenetics
Somatic Mutations in Noncoding Regions: Uncovering Their Impact on Tumor Progression and Therapy Resistance
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Shima Hasani,1,*
1. Department of Animal Biology, Faculty of Natural Sciences, The University of Tabriz, Tabriz, Iran.
- Introduction: Recent advances in cancer genomics have revealed that somatic mutations are not confined to protein-coding regions of the genome but are also prevalent in noncoding regions, including promoters, enhancers, and untranslated regions (UTRs). While the impact of coding mutations is well characterized, the functional consequences of noncoding mutations in cancer remain largely unexplored. These mutations may disrupt regulatory elements and alter gene expression, contributing to tumorigenesis and therapy resistance. This review aims to provide a comprehensive overview of the current understanding of somatic mutations in noncoding regions and their role in cancer progression and therapy resistance. We will discuss the mechanisms by which these mutations influence gene regulation, the latest techniques for identifying and characterizing these mutations, and their potential as therapeutic targets.
- Methods: A systematic review of the literature was conducted, focusing on studies published in the past decade that investigated somatic mutations in noncoding regions of the genome in various cancer types. Key databases were searched for relevant articles, and the findings were synthesized to highlight the emerging themes and gaps in the current knowledge.
- Results: Somatic mutations in noncoding regions have been identified in numerous cancers and are often associated with altered expression of oncogenes and tumor suppressor genes. These mutations can disrupt transcription factor binding sites, leading to aberrant gene expression and contributing to oncogenesis. Furthermore, mutations in regulatory elements have been implicated in resistance to targeted therapies by modulating the expression of genes involved in drug response. Advances in high-throughput sequencing and bioinformatics have enabled the identification of these mutations at an unprecedented scale, revealing their widespread impact across different cancer types. Somatic Mutations in Noncoding Regions: A New Frontier in Cancer Research Recent studies have uncovered numerous somatic mutations in noncoding regions of the genome, revealing their significant role in tumorigenesis and therapy resistance. These mutations often occur in regulatory elements such as enhancers, promoters, and long noncoding RNAs (lncRNAs), where they can profoundly alter gene expression and cellular behavior. 1. Enhancer Mutations in Melanoma: In a landmark study, somatic mutations were identified in the regulatory elements of the TERT gene, specifically in the promoter region, in various cancers including melanoma. These mutations create novel binding sites for E-twenty-six (ETS) transcription factors, leading to increased TERT expression and subsequent telomere elongation, which is a hallmark of cancer cells. The upregulation of TERT due to these promoter mutations supports the continuous proliferation of melanoma cells, highlighting the importance of noncoding mutations in driving oncogenesis. 2. Noncoding Mutations in TP53 Enhancer in Glioma: Recent work has identified recurrent mutations in an enhancer region of the TP53 gene in gliomas. These mutations were found to disrupt the binding of CTCF, a key architectural protein, thereby altering the chromatin landscape and leading to decreased TP53 expression. This reduction in TP53, a critical tumor suppressor, compromises the cell's ability to respond to DNA damage, facilitating tumor progression. The discovery of these enhancer mutations underscores their potential as biomarkers for glioma prognosis and as targets for therapeutic intervention. 3. LncRNA MALAT1 Mutations in Lung Cancer: The lncRNA MALAT1 has been extensively studied for its role in various cancers, and recent findings have shown that somatic mutations within the MALAT1 gene can contribute to lung cancer progression. These mutations have been linked to changes in the secondary structure of MALAT1, affecting its interaction with splicing factors and resulting in altered gene splicing. Such changes promote the expression of oncogenic splice variants, which drive lung cancer metastasis and resistance to chemotherapy. The modulation of MALAT1 function through targeted therapies could offer new avenues for treating lung cancer patients with these specific noncoding mutations. 4. Mutations in MYC Super-Enhancer in Breast Cancer: Another significant discovery involves mutations within the super-enhancer region of the MYC oncogene in breast cancer. These mutations increase the binding affinity for the transcription factor BRD4, leading to enhanced MYC expression. The overexpression of MYC is associated with aggressive tumor behavior and poor patient prognosis. Interestingly, inhibitors targeting BRD4 have shown promise in preclinical models, suggesting that these noncoding mutations could be exploited therapeutically to suppress MYC overactivity in breast cancer. 5. Intronic Mutations in BRAF and Therapy Resistance: Intronic mutations within the BRAF gene have been implicated in resistance to BRAF inhibitors in melanoma patients. These mutations are thought to create alternative splicing sites, resulting in the production of a truncated, but still active, form of the BRAF protein. This truncated protein lacks the domain targeted by the inhibitors, allowing melanoma cells to bypass the drug's effects and continue proliferating. This mechanism highlights the importance of noncoding regions in therapeutic resistance and the need for strategies that address these mutations.
- Conclusion: The noncoding genome plays a critical role in cancer development and resistance to therapy. Understanding the functional impact of somatic mutations in these regions is crucial for the development of novel therapeutic strategies. Future research should focus on integrating multi-omics data to map the regulatory networks affected by these mutations and on developing targeted interventions that can modulate the activity of mutated noncoding elements.
- Keywords: Somatic mutations, noncoding regions, cancer progression, therapy resistance, regulatory elements.
