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Author Spotlight: Impact of Intergenic Interactions on Disease-Identifying Dark Biomarkers
Published on: March 1, 2024
The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites,
Sven Diederichs1, Lorenz Bartsch2, Julia C Berkmann2
1Division of Cancer Research, Department of Thoracic Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany Division of RNA Biology & Cancer (B150), German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Consortium (DKTK), Freiburg, Germany s.diederichs@dkfz.de.
Abstract:
Cancer is a disease of the genome caused by oncogene activation and tumor suppressor gene inhibition. Deep sequencing studies including large consortia such as TCGA and ICGC identified numerous tumor-specific mutations not only in protein-coding sequences but also in non-coding sequences. Although 98% of the genome is not translated into proteins, most studies have neglected the information hidden in this "dark matter" of the genome. Malignancy-driving mutations can occur in all genetic elements outside the coding region, namely in enhancer, silencer, insulator, and promoter as well as in 5'-UTR and 3'-UTR Intron or splice site mutations can alter the splicing pattern. Moreover, cancer genomes contain mutations within non-coding RNA, such as microRNA, lncRNA, and lincRNA A synonymous mutation changes the coding region in the DNA and RNA but not the protein sequence. Importantly, oncogenes such as TERT or miR-21 as well as tumor suppressor genes such as TP53/p53, APC, BRCA1, or RB1 can be affected by these alterations. In summary, coding-independent mutations can affect gene regulation from transcription, splicing, mRNA stability to translation, and hence, this largely neglected area needs functional studies to elucidate the mechanisms underlying tumorigenesis. This review will focus on the important role and novel mechanisms of these non-coding or allegedly silent mutations in tumorigenesis.
Insights
Cancer arises from genomic mutations affecting both coding and non-coding DNA. This review highlights how mutations in the genome's "dark matter" drive cancer by altering gene regulation, impacting tumorigenesis.
Area of Science:
- Genomics
- Cancer Biology
- Molecular Oncology
Background:
- Cancer is fundamentally a genomic disease driven by genetic alterations.
- Large-scale sequencing projects (TCGA, ICGC) have identified numerous mutations in cancer genomes.
- Non-coding genomic regions, often termed the genome's "dark matter," are frequently overlooked despite their potential role in cancer.
Purpose of the Study:
- To review the significance of mutations in non-coding genomic elements in cancer development.
- To explore novel mechanisms by which these non-coding mutations contribute to tumorigenesis.
- To emphasize the need for functional studies on non-coding mutations.
Main Methods:
- Review of existing literature and deep sequencing data.
- Analysis of mutations in regulatory elements (enhancers, promoters, insulators) and non-coding RNAs.
- Examination of synonymous mutations and their impact on gene regulation.
Main Results:
- Mutations in non-coding regions (enhancers, promoters, UTRs, introns) can drive malignancy.
- Alterations in non-coding RNAs (microRNA, lncRNA) are implicated in cancer.
- Both oncogenes (TERT, miR-21) and tumor suppressor genes (TP53, BRCA1) can be affected by non-coding mutations.
Conclusions:
- Non-coding mutations significantly impact gene regulation, affecting transcription, splicing, mRNA stability, and translation.
- These "silent" mutations play a crucial role in tumorigenesis and warrant further investigation.
- Understanding non-coding mutations is essential for a comprehensive view of cancer genomics and potential therapeutic strategies.
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