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• W2296948836 abstract "Review18 March 2016Open Access The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations Sven Diederichs Corresponding Author Sven Diederichs Division 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 Search for more papers by this author Lorenz Bartsch Lorenz Bartsch German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Julia C Berkmann Julia C Berkmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Karin Fröse Karin Fröse German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Jana Heitmann Jana Heitmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Caroline Hoppe Caroline Hoppe German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Deetje Iggena Deetje Iggena German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Danny Jazmati Danny Jazmati German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Philipp Karschnia Philipp Karschnia German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Miriam Linsenmeier Miriam Linsenmeier German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Thomas Maulhardt Thomas Maulhardt German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Lino Möhrmann Lino Möhrmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Johannes Morstein Johannes Morstein German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Stella V Paffenholz Stella V Paffenholz German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Paula Röpenack Paula Röpenack German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Timo Rückert Timo Rückert German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Ludger Sandig Ludger Sandig German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Maximilian Schell Maximilian Schell German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Anna Steinmann Anna Steinmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Gjendine Voss Gjendine Voss German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Jacqueline Wasmuth Jacqueline Wasmuth German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Maria E Weinberger Maria E Weinberger German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Ramona Wullenkord Ramona Wullenkord German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Sven Diederichs Corresponding Author Sven Diederichs Division 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 Search for more papers by this author Lorenz Bartsch Lorenz Bartsch German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Julia C Berkmann Julia C Berkmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Karin Fröse Karin Fröse German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Jana Heitmann Jana Heitmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Caroline Hoppe Caroline Hoppe German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Deetje Iggena Deetje Iggena German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Danny Jazmati Danny Jazmati German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Philipp Karschnia Philipp Karschnia German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Miriam Linsenmeier Miriam Linsenmeier German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Thomas Maulhardt Thomas Maulhardt German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Lino Möhrmann Lino Möhrmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Johannes Morstein Johannes Morstein German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Stella V Paffenholz Stella V Paffenholz German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Paula Röpenack Paula Röpenack German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Timo Rückert Timo Rückert German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Ludger Sandig Ludger Sandig German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Maximilian Schell Maximilian Schell German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Anna Steinmann Anna Steinmann German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Gjendine Voss Gjendine Voss German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Jacqueline Wasmuth Jacqueline Wasmuth German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Maria E Weinberger Maria E Weinberger German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Ramona Wullenkord Ramona Wullenkord German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany Search for more papers by this author Author Information Sven Diederichs 1,2,3, Lorenz Bartsch4,‡, Julia C Berkmann4,‡, Karin Fröse4,‡, Jana Heitmann4,‡, Caroline Hoppe4,‡, Deetje Iggena4,‡, Danny Jazmati4,‡, Philipp Karschnia4,‡, Miriam Linsenmeier4,‡, Thomas Maulhardt4,‡, Lino Möhrmann4,‡, Johannes Morstein4,‡, Stella V Paffenholz4,‡, Paula Röpenack4,‡, Timo Rückert4,‡, Ludger Sandig4,‡, Maximilian Schell4,‡, Anna Steinmann4,‡, Gjendine Voss4,‡, Jacqueline Wasmuth4,‡, Maria E Weinberger4,‡ and Ramona Wullenkord4,‡ 1Division of Cancer Research, Department of Thoracic Surgery, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany 2Division of RNA Biology & Cancer (B150), German Cancer Research Center (DKFZ), Heidelberg, Germany 3German Cancer Consortium (DKTK), Freiburg, Germany 4German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany ‡These authors contributed equally to this work *Corresponding author. E-mail: [email protected] EMBO Mol Med (2016)8:442-457https://doi.org/10.15252/emmm.201506055 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info 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. Glossary Acceptor splice site Splice site at the end of an intron (3′ end). AU-rich elements (ARE) Conserved motif of adenine/uridine bases in the 3′-untranslated region (UTR) of an mRNA controlling mRNA decay. Branch point Sequence within the intron needed during splicing for the creation of the lariat structure. The adenine of the branch point forms a phosphodiester bond with the 5′ end of the intron. Cis-acting element A non-coding sequence in a gene or transcript with regulatory effects on the same or a nearby gene (in cis). Consensus splice site Nucleotide sequences that serve as splice sites in the majority of premature gene transcription. These include the highly conserved dinucleotides GT (5′ end of intron) and AG (3′ end of intron). Cryptic splice site Inactive splice site which can be activated when the previous dominant splice site loses its function. Donor splice site Splice site at the beginning of an intron (5′ end). Driver mutation Mutation that confers a growth advantage for the tumor leading to malignant initiation, promotion, or progression. Epigenetic events Events of gene regulation without underlying alterations in the DNA sequence, for example, through DNA methylation or histone modification. Enhancer Transcription factor binding site located up to 1 Mbp up- or downstream of a particular gene with bidirectional effects. The binding of a transcription factor to an enhancer results in the upregulation of the transcription of the respective gene. Exon skipping Exons are sequences that are usually retained during the splicing process and are part of the mature transcript. Exon skipping denotes a form of alternative splicing in which an exon and its neighboring introns are spliced out, for example, due to mutations in or different strengths of splice sites. Insulator Genomic region that creates a boundary between an enhancer and neighboring genes. Enhancer-blocking insulators limit the number of genes which an enhancer can influence through selective disruption of enhancer–promoter interaction. Internal ribosome entry site (IRES) Alternate ribosomal binding site (RBS) in mRNA, downstream of the classic RBS at the 5′ cap. Intron retention Introns are sequences that are usually cut out during the splicing process and are not part of the mature transcript. Intron retention denotes a form of alternative splicing in which whole or parts of introns remain in the RNA, for example, due to mutations in or different strengths of splice sites. Kozak consensus sequence A nucleotide sequence motif in mRNA essential for ribosomal assembly and initiation of translation around the start codon. Long non-coding RNA (lncRNA) Long non-coding RNAs are non-coding transcripts with a length of > 200 nucleotides and lacking a significant coding potential. LncRNAs affect a variety of cellular functions: they regulate gene expression, influence the activity and localization of proteins or nucleic acids, or act as scaffolds for the formation of cellular substructures and protein complexes. microRNA (miRNA) Short, non-coding RNA (18–25 nt) that can repress gene expression at the post-transcriptional level by binding to mRNAs. NCI-60 Panel A panel of the US National Cancer Institute comprising 60 different, well-characterized human cancer cell lines that is used to test natural and chemical products and serves as a tool in cancer research. Passenger mutations Mutation that does not promote the fitness of malign cells or even damage them. PIWI-interacting RNAs or piRNAs A class of small non-coding RNAs mainly involved in the silencing of transposable elements (TEs) in germ cells. Polyadenylation After cleavage of a pre-mRNA at its 3′-end to terminate the transcript, roughly 250 adenosines are attached to the mRNA sequence that form the poly(A) tail ensuring translational efficacy and increasing mRNA stability. Promoter Region of DNA located within the close upstream area of a gene that contains binding sites for specific transcription factors crucial for the initiation of transcription. Seed region Nucleotides 2–8 of a microRNA largely determining target recognition by usually perfect complementarity to the target mRNA. Single nucleotide polymorphism (SNP) Single nucleotide variation in the genome that is found in at least 1% of the population. Silent mutation Base substitution anywhere in the genome without any effect on the amino acid sequence of coding genes, for example, mutations outside of genes or in regulatory elements or synonymous mutations. Synonymous mutation Base substitution in the coding sequence of a protein-coding gene that does not modify the amino acid sequence of the gene product due to the redundancy of the genetic code. Trans-acting element A factor, usually a protein or oligonucleotide, with regulatory effects on a gene distant from its transcriptional source (in trans). Upstream open reading frame (uORF) Open reading frame in the 5′-UTR with regulatory effects on the translation of the main ORF downstream on the same mRNA Introduction Cancer remains one of the leading causes of death worldwide according to the World Cancer Report 2014 (Stewart & Wild, 2014). Already in 1902, Theodor Boveri speculated that cancer might be a disease of the genome (Boveri, 2008). Research of the last decades confirmed this hypothesis and deepened our understanding of the genomic landscape of cancer (Alexandrov et al, 2013; Weinstein et al, 2013). We now know that a broad spectrum of molecular events can drive tumorigenesis. Genetic events range from amplifications, deletions, insertions, translocations, loss of heterozygosity to missense, non-sense, or frameshift point mutations (Stratton et al, 2009; Vogelstein et al, 2013). Both, activated oncogenes and inactivated tumor suppressor genes, can contribute to tumorigenesis and progression by conferring tumor-specific properties, called the hallmarks of cancer (Hanahan & Weinberg, 2000). Also epigenetic events and infectious agents as the human papillomavirus can have a tumorigenic effect, but these are beyond the scope of this review (zur Hausen, 2009; Baylin & Jones, 2011). Although substantial progress in understanding of the cancer driver events has led to the development of new targeted therapeutics (Druker et al, 2001a; Sordella et al, 2004), the last decade of research has revealed that the genomic landscape of cancer is substantially more complex than previously assumed. This has been largely driven by the introduction of high-throughput next-generation sequencing techniques, which unravel the extensive mutational heterogeneity of tumors (Leiserson et al, 2015). These techniques allow rapid sequencing of a large number of complete genomes so that an increasing amount of cancer genome data becomes available (Kandoth et al, 2013). International consortia are involved in the generation and structuring of the abundance of information (Lawrence et al, 2013). The Cancer Genome Atlas (TCGA) Research Network aims to analyze molecular tumor profiles, for example, by detecting patterns across different types of cancer (Weinstein et al, 2013). The International Cancer Genome Consortium (ICGC) coordinates large-scale cancer genome studies at the genomic, epigenomic, and transcriptomic levels. Over 25,000 genomes from 50 different cancer types are being sequenced to improve therapy, prognosis, and discovery of new targets (ICGC, 2010). For example, the identification of new mechanisms contributing to medulloblastoma tumorigenesis led to novel targets for therapy (Jones et al, 2012). These large-scale approaches show a large number of different mutations (Wood et al, 2007), but dissecting the role of individual mutations in this landscape as either driver or passenger mutations will pose the next challenge (Kandoth et al, 2013; Weinstein et al, 2013). So far, cancer research has mostly focused on mutations that alter protein-coding sequences. For example, the standard Catalogue Of Somatic Mutations In Cancer (COSMIC) only lists aberrations in the coding sequences of genes (Forbes et al, 2008). However, this coding fraction only represents less than 2% of the human genome (Weinhold et al, 2014). Indeed, the vast majority of the genomic sequence is either transcribed into non-coding RNAs or comprised of regulatory elements (Alexander et al, 2010). Nevertheless, this part of the genome has been mostly neglected as irrelevant for decades despite early examples of functional relevance, for example, of the non-coding RNAs MALAT1 (Ji et al, 2003; Gutschner et al, 2013) or H19 (Gabory et al, 2006) (a comprehensive list of all gene names used in the review is provided in Table EV1). The huge amount of sequence data now available provides the chance to explore the role of this dark matter in cancer genomes. In this review, we give a comprehensive overview on genetic aberrations not altering coding information and highlight the mechanisms whereby they nevertheless affect tumorigenesis. These include synonymous mutations as well as mutations in regulatory elements, untranslated regions, splice sites, and non-coding RNAs. Regulatory elements Functional mutations in regulatory regions, such as promoters and enhancers, can either create or destruct transcription factor (TF) binding sites. Additionally, structural aberrations such as translocations, deletions, insertions, or duplications can alter the interaction between regulatory elements and the coding genes they control. For example, strong promoters or enhancers brought into proximity of MYC or PAX5 can activate these oncogenes (Busslinger et al, 1996; Gerbitz et al, 1999). Mutations occurring in regulatory regions—depending on whether the binding site of an activating or repressing transcription factor is affected—can result in transcriptional up- or downregulation. If oncogenes or tumor suppressor genes are affected, mutations in regulatory elements may constitute causative events in tumorigenesis. In 2013, a promoter mutation was discovered in the telomerase reverse transcriptase (TERT) gene in melanoma patients (Horn et al, 2013). TERT encodes the catalytic subunit of telomerase, an enzyme that preserves the chromosomal ends, which would otherwise be shortened in each cell division. Aberrant TERT expression results in a limitless proliferative potential, a hallmark of cancer (Hanahan & Weinberg, 2000). The somatic transitions C228T and C250T in the TERT promoter do not only occur in melanoma, but strikingly in numerous malignancies such as hepatocellular carcinoma (HCC) and are among the most frequent mutations in cancer (Vinagre et al, 2013; Totoki et al, 2014; Weinhold et al, 2014; Melton et al, 2015). These mutations create a novel binding site for the ETS transcription factor GABP in the TERT promoter leading to an increased transcriptional activity (Bell et al, 2015). Consequently, these mutations constitute an important step in tumorigenesis. In addition, a synergistic interaction of the TERT promoter mutations with the BRAF V600E mutation that induces the ETS transcription factor possesses clinical relevance (Xing et al, 2014). Moreover, the mutated TERT promoter is a candidate biomarker for recurrence detection of urothelial carcinoma and thus constitutes a novel diagnostic tool (Kinde et al, 2013). Mutations in regulatory regions can also cause the downregulation of tumor suppressors. In melanoma, three recurrent C > T transitions within the promoter region of the tumor suppressor gene SDHD disrupt ETS binding sites decreasing its transcription rate. These somatic promoter mutations correlate with a shorter overall survival in melanoma patients (Weinhold et al, 2014). Enhancer mutations can likewise increase transcriptional levels of oncogenes. In T-cell acute lymphoblastic leukemia (T-ALL), a somatic heterozygous insertion creates a binding site for the transcription factor MYB. Thereby, a large regulatory element, a so-called “super-enhancer”, is created leading to the overexpression of the oncogene TAL1 (Mansour et al, 2014). Another recent example is the germline single nucleotide polymorphism (SNP) rs2168101 G > T in a super-enhancer within the first intron of LMO1. The G allele of this SNP constitutes a transcription factor binding site in the super-enhancer that drives the expression of the oncogene LMO1 and predisposes to neuroblastoma (Oldridge et al, 2015). The term super-enhancer describes a large enhancer with extraordinarily high transcription factor enrichment (Pott & Lieb, 2015). Such super-enhancers may serve as tumor-specific targets and promising results have emerged in multiple myeloma, where selective super-enhancer inhibition caused loss of oncogene expression (Loven et al, 2013). Vice versa, downregulating mutations exist in enhancers. For example, the enhancer of the B-cell differentiation factor PAX5 is disrupted by somatic mutations, impairing the maturation of B cells and promoting chronic lymphocytic leukemia (CLL) (Puente et al, 2015). Lastly, deletions can also affect insulator regions. Deregulation of the H19/IGF2 locus causes the Beckwith–Wiedemann syndrome, which can give rise to embryonic tumors such as Wilms' tumors. Germline microdeletions within the regulatory region of the H19/IGF2 locus can affect the insulator function resulting in reversed enhancement of two genes (Sparago et al, 2004; Ideraabdullah et al, 2014). In addition to the examples described above, other mutations and especially polymorphisms in regulatory regions of cancer genes are associated with tumorigenesis (Table 1). Table 1. Alterations within regulatory DNA elements Genetic event Regulation Affected gene Gene function Alteration Reference New binding site for activating TF ↑ TERT (M) Catalytic subunit of telomerase C228T, C250T (promoter) Bell et al (2015); Heidenreich et al (2014); Horn et al (2013) TAL1 (M) Oncogene, transcription factor insertion (super-enhancer) Mansour et al (2014) MCL1 (M) Apoptosis inhibitor insertion (promoter) Moshynska et al (2004); Tobin et al (2005) CCND1 (P) Oncogene, regulation of cell cycle progression multiple SNPs (enhancer) Schodel et al (2012) MMP1 (P) MMP (−1,607) 1G/2G (promoter) Liu et al (2012) HGF (P) Cell proliferation, survival, migration, and morphogenesis truncation deletion (promoter) Ma et al (2009b) LMO1 (P) Transcription factor SNP in super-enhancer Oldridge et al (2015) New binding site for repressing TF ↓ BRM (P) Cancer susceptibility gene insertion (−741, −1,321) (promoter) Gao et al (2013); Liu et al (2011); Wong et al (2014) Disrupted binding site for activating TF ↓ SDHD (M) Tumor suppressor gene, subunit of succinate dehydrogenase complex 3 hotspots C > T (promoter) Weinhold et al (2014) WDR74 (M) Cell cycle control, apoptosis 52 hotspots C > T (promoter) Weinhold et al (2014) PAX5 (M) B cell differentiation factor multiple mutations (enhancer) Puente et al (2015) CK-19 (M) Tumor marker (NSCLC) G (−99)C (promoter) Fujita et al (2001) MMP2 (P) MMP C (−1,306)T (promoter) Liu et al (2012) Disrupted binding site for repressing TF ↑ AMACR (P) Racemase in fat metabolism germline deletion (promoter) Zhang et al (2009b) Disrupted insulator ↑/↓ IGF2/H19 (M) Proliferation control germline deletion (insulator) Ideraabdullah et al (2014); Sparago et al (2004) Unknown ↓ PLEKHS1 (M) Largely unknown 23 hotspots C > T (promoter) Weinhold et al (2014) ↓ CASP8 (P) Induction of apoptosis −652 6N del (promoter) de Martino et al (2013); Li et al (2010); Malik et al (2011); Wang et al (2009) ↑ NFKB1 (P) Transcription factor insertion (promoter) Fan et al (2011); Mohd Suzairi et al (2013); Tang et al (2010); Zhang et al (2009a) ↓ BRCA1 (P) Tumor suppressor, DNA repair gene 5-kb deletion (promoter + 5′-UTR) Brown et al (2002) ↓ MMP3 (P) MMP (−1,171) 5A/6A (promoter) Liu et al (2012) ↑ MMP7 (P) MMP A (−181)G (promoter) Liu et al (2012) ↑ MMP9 (P) MMP C (−1,562)T (promoter) Liu et al (2012) Mutations are marked with (M); polymorphisms are marked with (P). TF, transcription factor; MMP, matrix metalloproteinase. 5′-Untranslated regions (5′-UTR) The untranslated regions (UTRs) flanking the coding region in mature messenger RNA (mRNA) regulate translation or mRNA stability through diverse mechanisms (Fig 1, Table 2). Trans-acting RNA binding proteins (RBPs) and small RNAs can bind to either simple sequence elements or secondary and tertiary structures of the 5′-UTR as well as the 3′-UTR (reviewed in Di Liegro et al, 2014). Figure 1. Schematic depiction of mutations within the 5′- and 3′-UTRMutations can alter the secondary structure of the 5′- or 3′-UTR or occur in RNA binding protein (RBP) binding sites, upstream ORFs (uORF), internal ribosome entry sites (IRES; ITAF: IRES trans-acting factor), start codons of open reading frames (ORF), microRNA binding sites, or polyadenylation signals (polyA). These alterations can affect translation efficiency, mRNA stability, ORF length, or RBP interaction as well as cause alternative cleavage and polyadenylation (APA). Prominent examples of genes involved in tumorigenesis (green: induced, red: decreased) that exhibit mutations (red star) in such elements are illustrated. Download figure Download PowerPoint Table 2. Mutations and SNPs in 5′-UTR elements associated with cancer Gene Variant Regulatory element/Mechanism Effect on protein Cancer type Reference CDKN1B 4-bp deletion C.-456-453del (g) uORF Decrease MEN4 Occhi et al (2013) CDKN2A G-34T (g) Aberrant initiation codon N/A Melanoma Liu et al (1999) C-MYC C2756T (s) IRES Increase Multiple myeloma Chappell et al (2000) ERCC5 A25G (SNP) uORF Increase Pediatric ependymoma Somers et al (2015) RAD51 G135C (SNP) Splice site/secondary structure Decrease Breast cancer Antoniou et al (2007) RB1 G17C, G18U (SNV, N/A) Secondary structure Decrease Retinoblastoma Kutchko et al (2015) TP53 C119T (SNP) IRES Decrease Melanoma Khan et al (2013); Soto et al (2005) Mutational status as indicated in (); s, somatic; g, germline; N/A, not available; SNP, single nucleotide polymorphism; SNV, single nucleotide variant. Cis-acting elements in the 5′-UTR mediate translational regulation via the 5′-cap or the secondary structure. Stable 5′-UTR structures impede translation by reducing the accessibility for the translational machinery and ribosomal scanning. For example, mutations in RB1 stabilize the 5′-UTR secondary structures and are likely conducive to retinoblastoma (Kutchko et al, 2015). In addition, mutations in the Kozak consensus sequence can lead to leaky scanning and reduced translation initiation, for example, a somatic mutation in BRCA1 in breast cancer (Signori et al, 2001; Wang et al, 2007" @default.
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• W2296948836 title "The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non‐coding <scp>RNA</scp> and synonymous mutations" @default.
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