Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Jun 1;25(10):1828-1838.
doi: 10.2741/4879.

Beyond the coding genome: non-coding mutations and cancer

Kaivalya Walavalkar  1 , Dimple Notani  2
Affiliations
Review

Beyond the coding genome: non-coding mutations and cancer

Kaivalya Walavalkar et al. Front Biosci (Landmark Ed). .

Abstract

Latest advancements in genomics involving individuals from different races and geographical locations has led to the identification of thousands of common as well as rare genetic variants and copy number variations (CNVs). These studies have surprisingly revealed that the majority of genetic variation is not present within the coding region but rather in the non-coding region of the genome, which is also termed as "Medical Genome". This short review describes how mutations/variations within; regulatory sequences, architectural proteins and transcriptional regulators give rise to the aberrant gene expression profiles that drives cellular transformations and malignancies.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Structural mutations in enhancers: (i) IGFBP5 gene is regulated by its enhancer. When a small stretch in the enhancer is deleted which harboured the CTCF motif, the enhancer activity from the region is lost and gene is down-regulated. IGFBP5 being a tumour-suppressor gene leads to increased risk of cancer. (ii) An oncogene TAL1, has some basal expression in the wild type condition. Mutations lead to the gain of Myb motifs which facilitate the birth of a super-enhancer which up-regulates TAL1 expression and thus leading to increased susceptibility to cancer. (iii) Mutations in the enhancer of AR gene lead to the amplification of the region harbouring the enhancer which leads to increased expression of androgen receptor leading to increased prostate cancer risk. (iv) An enhancer is present physically far from the TERT gene. Rearrangement places the enhancer in close physical proximity to the TERT oncogene leading to its activation.
Figure 2
Figure 2
Single nucleotide polymorphism in enhancers: (i) A Single nucleotide polymorphism (SNP) leads to the birth of an enhancer. In the non-risk allele, the target gene is not regulated by any enhancer, but upon the gain of the risk allele of the SNP, an enhancer is born which targets the gene leading to its higher expression than normal levels. When such a gene is an oncogene, its upregulation might prove to be tumorigenic. (ii) An enhancer which targets its cognate gene possesses a SNP, the risk allele of which leads to the death of the enhancer and heterochromatinization of the enhancer region. This leads to the down-regulation of the gene and when this gene is a tumour-suppressor gene, it increases the susceptibility to cancer. (iii) An enhancer which targets its cognate gene, if possesses a risk SNP which leads to the gain of binding of a transcription activator leading to an up-regulation of the oncogene hence, susceptibility to cancer. (iv) An enhancer which targets its cognate gene, if possesses a risk SNP which leads to the gain of a different transcription factor than the one which was binding when the wildtype allele of the SNP was present. The new transcription factor is more potent in its activation of the enhancer and the target oncogene gets upregulated leading to cancer susceptibility.
Figure 3
Figure 3
Mutations and insulator: An insulator separates two TADs; one active and the other repressed, harbouring active and repressed genes respectively. When there is a mutation in the insulator and/or a transcription factor (like CTCF) which binds to the insulator such that the insulator function is lost, the adjacent TADs merge and all the genes show a similar pattern of expression, active expression in this case.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Zhang W, Bojorquez-Gomez A, Velez DO, Xu G, Sanchez KS, Shen JP, Chen K, Licon K, Melton C, Olson KM, Yu MK. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nat genet. 2018;50(4):613. doi: 10.1038/s41588-018-0091-2. - DOI - PMC - PubMed
    1. Jolly MK, Ware KE, Gilja S, Somarelli JA, Levine H. EMT and MET: necessary or permissive for metastasis? Mol Oncol. 2017;11(7):755–769. doi: 10.1002/1878-0261.12083. - DOI - PMC - PubMed
    1. Corradin O, Scacheri PC. Enhancer variants: evaluating functions in common disease. Genome med. 2014;6(10):85. doi: 10.1186/s13073-014-0085-3. (1-14. - DOI - PMC - PubMed
    1. Hazelett DJ, Rhie SK, Gaddis M, Yan C, Lakeland DL, Coetzee SG, Henderson BE, Noushmehr H, Cozen W, Kote-Jarai Z, Eeles RA. Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS genet. 2014;10(1):e1004102. doi: 10.1371/journal.pgen.1004102. - DOI - PMC - PubMed
    1. Bonifer C, Cockerill PN. Chromatin priming of genes in development: concepts, mechanisms and conse-quences. Exp hematol. 2017;49:1–8. doi: 10.1016/j.exphem.2017.01.003. - DOI - PubMed

Publication types

LinkOut - more resources