title: Mutated tumor alleles are expressed according to their DNA frequency.
abstract: The transcription of tumor mutations from DNA into RNA has implications for biology, epigenetics and clinical practice. It is not clear if mutations are in general transcribed and, if so, at what proportion to the wild-type allele. Here, we examined the correlation between DNA mutation allele frequency and RNA mutation allele frequency. We sequenced the exome and transcriptome of tumor cell lines with large copy number variations, identified heterozygous single nucleotide mutations and absolute DNA copy number, and determined the corresponding DNA and RNA mutation allele fraction. We found that 99% of the DNA mutations in expressed genes are expressed as RNA. Moreover, we found a high correlation between the DNA and RNA mutation allele frequency. Exceptions are mutations that cause premature termination codons and therefore activate nonsense-mediated decay. Beyond this, we did not find evidence of any wide-scale mechanism, such as allele-specific epigenetic silencing, preferentially promoting mutated or wild-type alleles. In conclusion, our data strongly suggest that genes are equally transcribed from all alleles, mutated and wild-type, and thus transcribed in proportion to their DNA allele frequency.
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: John C
authors.initials: JC
authors.lastname: Castle
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Loewer
authors.affiliation: 1] TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany [2] University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Boegel
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Arbel D
authors.initials: AD
authors.lastname: Tadmor
authors.affiliation: 1] TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany [2] BioNTech AG, Kupferbergterrasse 17-19, 55131 Mainz, Germany.
authors.forename: Valesca
authors.initials: V
authors.lastname: Boisguerin
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Jos
authors.initials: J
authors.lastname: de Graaf
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Paret
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.affiliation: TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
authors.affiliation: University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.affiliation: 1] TRON gGmbH - Translational Oncology at Johannes Gutenberg-University Medical Center gGmbH, Langenbeckstr. 1, Building 708, 55131 Mainz, Germany [2] University Medical Center of the Johannes Gutenberg-University Mainz, 55131, Mainz, Germany [3] BioNTech AG, Kupferbergterrasse 17-19, 55131 Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*
references.citation: Nucleic Acids Res. 2012 Jul;40(13):e104
references.pmid: 22467206
references.citation: Science. 2006 Oct 13;314(5797):268-74
references.pmid: 16959974
references.citation: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D29-31
references.pmid: 16381868
references.citation: Annu Rev Biochem. 2007;76:51-74
references.pmid: 17352659
references.citation: J Clin Oncol. 2009 Apr 20;27(12):2091-6
references.pmid: 19188670
references.citation: Nat Rev Genet. 2002 Apr;3(4):285-98
references.pmid: 11967553
references.citation: Bioinformatics. 2013 Jan 1;29(1):15-21
references.pmid: 23104886
references.citation: Cancer Res. 2012 Mar 1;72(5):1081-91
references.pmid: 22237626
references.citation: PLoS One. 2009 Oct 14;4(10):e7464
references.pmid: 19826477
references.citation: Nat Rev Genet. 2010 Aug;11(8):533-8
references.pmid: 20567245
references.citation: Bioinformatics. 2012 Feb 1;28(3):311-7
references.pmid: 22155872
references.citation: Bioinformatics. 2009 Jul 15;25(14):1754-60
references.pmid: 19451168
references.citation: Nature. 2007 Mar 8;446(7132):153-8
references.pmid: 17344846
references.citation: Int J Cancer. 2011 Jun 15;128(12):2872-80
references.pmid: 20824714
references.citation: BMC Genomics. 2014 Mar 13;15:190
references.pmid: 24621249
references.citation: Nat Biotechnol. 2012 May;30(5):413-21
references.pmid: 22544022
references.citation: Proc Natl Acad Sci U S A. 2010 Sep 28;107(39):16910-5
references.pmid: 20837533
references.citation: Nat Biotechnol. 2013 Mar;31(3):213-9
references.pmid: 23396013
references.citation: BMC Genomics. 2013 Aug 07;14:536
references.pmid: 23919664
references.citation: Curr Biol. 2008 Nov 25;18(22):1735-41
references.pmid: 19026546
references.citation: PLoS One. 2010 Feb 19;5(2):e9317
references.pmid: 20174472
references.citation: Nature. 2013 Aug 8;500(7461):207-11
references.pmid: 23925245
references.citation: PLoS One. 2012;7(8):e41551
references.pmid: 22916110
references.citation: Nature. 2013 Aug 22;500(7463):415-21
references.pmid: 23945592
references.citation: Genome Res. 2012 Mar;22(3):568-76
references.pmid: 22300766
references.citation: Bioinformatics. 2009 Aug 15;25(16):2078-9
references.pmid: 19505943
references.citation: BMC Genomics. 2010 Apr 16;11:244
references.pmid: 20398377
references.citation: Genome Res. 2012 Oct;22(10):1995-2007
references.pmid: 22637570
references.citation: Cell. 2012 May 25;149(5):994-1007
references.pmid: 22608083
references.citation: PLoS One. 2009;4(2):e4576
references.pmid: 19238210
references.citation: BMC Genomics. 2012 Apr 12;13 Suppl 2:S6
references.pmid: 22537301
references.citation: Cancer Res. 2004 May 1;64(9):3060-71
references.pmid: 15126342