Original article| Volume 206, ISSUE 6, P222-226, June 2013

The importance of codon context for understanding the Ig-like somatic hypermutation strand-biased patterns in TP53 mutations in breast cancer

      Evidence already exists that the activation-induced deaminase (AID)/APOBEC family constitutes a set of differentially expressed enzymes capable of deaminating cytosines (C to U) in single-stranded DNA (ssDNA) and that they are potentially powerful mutagens. The mutagenic processes involved are believed to be activated in many nonlymphoid tissue types—for example, initiating some cancers and/or leading to further somatic mutagenesis. To investigate the extent that codon context might be important in influencing the likely location of TP53 mutations in breast cancer, the codon-bias patterns resulting from the ssDNA target specificities of cytidine deaminases of the AID/APOBEC family were analyzed. The data indicate that codon context strongly influences the likely location of mutations at motifs for AID/APOBEC1/APOBEC3G, and at WA sites. An unexpected finding is a highly significant preference for transitions of cytosine to occur at the first nucleotide position and for transitions of guanosine to occur at the second nucleotide position in the mutated codon (read 3′ to 5′). Thus, the mechanisms involved appear to be sensitive to codon reading frames and to have an intrinsic ability to differentiate between the cytosines on the nontranscribed strand and those on the transcribed strand in the context of an open “transcription bubble.”


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        • Pfeifer G.P.
        • Besaratinia A.
        Mutational spectra of human cancer.
        Hum Genet. 2009; 125: 493-506
        • Steele E.J.
        • Lindley R.A.
        Somatic mutation patterns in non-lymphoid cancers resemble the strand biased somatic hypermutation spectra of antibody genes.
        DNA Repair. 2010; 9: 600-603
        • Lindley R.A.
        • Steele E.J.
        Critical analysis of strand-biased somatic mutation signatures in TP53 versus Ig genes, in genome-wide data and the etiology of cancer.
        ISRN Genomics. 2013; 2013: 1-18
        • Beale R.C.L.
        • Petersen-Mahrt S.K.
        • Watt I.N.
        • et al.
        Comparison of the different context-dependence of DNA deamination by APOBEC enzymes: Correlation with mutation spectra in vivo.
        J Mol Biol. 2004; 337: 585-594
        • Okazaki I.M.
        • Hiai H.
        • Kakazu N.
        • et al.
        Constitutive expression of AID leads to tumorigenesis.
        J Exp Med. 2003; 197: 1173-1181
        • Honjo T.
        • Kobayashi M.
        • Begum N.
        The AID dilemma: infection or cancer?.
        Adv Cancer Res. 2012; 113: 1-44
        • Petitjean A.
        • Mathe E.
        • Kato S.
        • et al.
        Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53 database.
        Hum Mutat. 2007; 28: 622-629
        • Hainaut R.
        • Pfeiffer G.P.
        Patterns of p53 G->T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke.
        Carcinogenesis. 2001; 22: 367-374
        • Pauklin IV,
        • Semiandez G.
        • Bachmann A.R.
        • et al.
        Estrogen directly activates AID transcription and function.
        J Exp Med. 2009; 206: 99-111
        • Rogozin I.B.
        • Malyarchuk B.A.
        • Pavlov Y.
        • et al.
        From context-dependence of mutations to molecular mechanisms of mutagenesis.
        Pac Symp Biocomput. 2005; : 409-420
        • Soussi T.
        Advances in carcinogenesis: A historical perspective from observational studies to tumour genome sequencing and TP53 mutation spectrum analysis.
        Biochem Biophysics Acta. 2011; 1816: 199-208
        • Chang Y.F.
        • Imam J.S.
        • Wilkinson M.F.
        The nonsense-mediated decay RNA surveillance pathway.
        Ann Rev Biochem. 2007; 76: 51-74
        • Pham P.
        • Bransteitter R.
        • Petruska J.
        • et al.
        Processive AID-catalysed cytosine deamination on single-stranded DNA stimulates somatic-hypermutation.
        Nature. 2003; 424: 103-107