title: The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non-coding RNA and synonymous mutations.
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.
authors.affiliation: 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 s.diederichs@dkfz.de.
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Bartsch
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Berkmann
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Fröse
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Heitmann
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hoppe
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Deetje
authors.initials: D
authors.lastname: Iggena
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Danny
authors.initials: D
authors.lastname: Jazmati
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Karschnia
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Linsenmeier
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Maulhardt
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Lino
authors.initials: L
authors.lastname: Möhrmann
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Morstein
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Stella V
authors.initials: SV
authors.lastname: Paffenholz
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Paula
authors.initials: P
authors.lastname: Röpenack
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Rückert
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Sandig
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schell
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Steinmann
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Gjendine
authors.initials: G
authors.lastname: Voss
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wasmuth
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Weinberger
authors.affiliation: German Academic Scholarship Foundation - Studienstiftung des deutschen Volkes, Bonn, Germany.
authors.forename: Ramona
authors.initials: R
authors.lastname: Wullenkord
mesh_terms: D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D012326:RNA Splicing; D022661:RNA, Untranslated; D012045:Regulatory Sequences, Nucleic Acid; D000069456:Silent Mutation; D020506:Untranslated Regions
chemical_list: D022661:RNA, Untranslated; D020506:Untranslated Regions
keywords: alternative polyadenylation; enhancer; mutation; non‐coding RNA; synonymous mutation