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The dark matter of the cancer genome : Aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations

Diederichs, Sven ; Bartsch, Lorenz ; Berkmann, Julia C. ; Fröse, Karin ; Heitmann, Jana ; Hoppe, Caroline ; Iggena, Deetje ; Jazmati, Danny ; Karschnia, Philipp and Linsenmeier, Miriam , et al. (2016) In EMBO Molecular Medicine 8(5). p.442-457
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,... (More)

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. Coding-independent mutations affect gene regulation from transcription, splicing, mRNA stability to translation. This one of a kind review discusses the largely neglected impact of this genome "dark matter" on tumorigenesis.

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publishing date
type
Contribution to journal
publication status
published
keywords
Alternative polyadenylation, Enhancer, Mutation, Non-coding RNA, Synonymous mutation
in
EMBO Molecular Medicine
volume
8
issue
5
pages
442 - 457
publisher
Wiley-Blackwell
external identifiers
  • pmid:26992833
  • scopus:84961233931
ISSN
1757-4676
DOI
10.15252/emmm.201506055
language
English
LU publication?
no
additional info
Publisher Copyright: © 2016 EMBO.
id
6c6f3b61-407c-4985-9a3d-ec1e0e93eddb
date added to LUP
2025-12-02 09:02:11
date last changed
2025-12-03 03:22:48
@article{6c6f3b61-407c-4985-9a3d-ec1e0e93eddb,
  abstract     = {{<p>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. Coding-independent mutations affect gene regulation from transcription, splicing, mRNA stability to translation. This one of a kind review discusses the largely neglected impact of this genome "dark matter" on tumorigenesis.</p>}},
  author       = {{Diederichs, Sven and Bartsch, Lorenz and Berkmann, Julia C. and Fröse, Karin and Heitmann, Jana and Hoppe, Caroline and Iggena, Deetje and Jazmati, Danny and Karschnia, Philipp and Linsenmeier, Miriam and Maulhardt, Thomas and Möhrmann, Lino and Morstein, Johannes and Paffenholz, Stella V. and Röpenack, Paula and Rückert, Timo and Sandig, Ludger and Schell, Maximilian and Steinmann, Anna and Voss, Gjendine and Wasmuth, Jacqueline and Weinberger, Maria E. and Wullenkord, Ramona}},
  issn         = {{1757-4676}},
  keywords     = {{Alternative polyadenylation; Enhancer; Mutation; Non-coding RNA; Synonymous mutation}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{442--457}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{The dark matter of the cancer genome : Aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations}},
  url          = {{http://dx.doi.org/10.15252/emmm.201506055}},
  doi          = {{10.15252/emmm.201506055}},
  volume       = {{8}},
  year         = {{2016}},
}