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The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis

View Article: PubMed Central - PubMed

ABSTRACT

Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B- breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B- tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature' mutations in cancer.

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A3H haplotype I accounts for APOBEC signature mutations in A3B- breast tumours.(a) Schematic of A3A, A3B and the A3A-B fusion gene. Exons are numbered and indicated by boxes, and coding regions are shaded. A 5 kbp scale is indicated. (b) Schematic of the A3H gene with haplotype-defining amino acid variants and SNP numbers listed below. Labelled as in a, except the scale indicates 2.5 kbp. (c) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B+/+ and A3B−/− breast tumors with n-values and total mutation numbers in parentheses. C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively. (d) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B−/− breast cancers with the indicated A3H haplotype combinations (n-values and total mutation numbers in parentheses). C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively.
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f1: A3H haplotype I accounts for APOBEC signature mutations in A3B- breast tumours.(a) Schematic of A3A, A3B and the A3A-B fusion gene. Exons are numbered and indicated by boxes, and coding regions are shaded. A 5 kbp scale is indicated. (b) Schematic of the A3H gene with haplotype-defining amino acid variants and SNP numbers listed below. Labelled as in a, except the scale indicates 2.5 kbp. (c) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B+/+ and A3B−/− breast tumors with n-values and total mutation numbers in parentheses. C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively. (d) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B−/− breast cancers with the indicated A3H haplotype combinations (n-values and total mutation numbers in parentheses). C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively.

Mentions: To test the hypothesis that stable forms of A3H (haplotypes II, V and VII) contribute to breast cancer mutagenesis in the absence of A3B, we computationally screened and manually confirmed all available breast tumour data sets from TCGA to identify specimens with two copies of the A3B deletion allele, deduce A3H haplotypes and assess association with APOBEC signature mutations (gene schematics in Fig. 1a,b). A total of 17 A3B- tumours were identified and, as reported previously from analyses of 13 -tumours44, the overall APOBEC signature in these tumours is visibly more pronounced than the composite cytosine mutation spectrum from 577 breast tumours with two confirmed intact copies of A3B (boxed in Fig. 1c).


The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
A3H haplotype I accounts for APOBEC signature mutations in A3B- breast tumours.(a) Schematic of A3A, A3B and the A3A-B fusion gene. Exons are numbered and indicated by boxes, and coding regions are shaded. A 5 kbp scale is indicated. (b) Schematic of the A3H gene with haplotype-defining amino acid variants and SNP numbers listed below. Labelled as in a, except the scale indicates 2.5 kbp. (c) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B+/+ and A3B−/− breast tumors with n-values and total mutation numbers in parentheses. C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively. (d) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B−/− breast cancers with the indicated A3H haplotype combinations (n-values and total mutation numbers in parentheses). C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5036005&req=5

f1: A3H haplotype I accounts for APOBEC signature mutations in A3B- breast tumours.(a) Schematic of A3A, A3B and the A3A-B fusion gene. Exons are numbered and indicated by boxes, and coding regions are shaded. A 5 kbp scale is indicated. (b) Schematic of the A3H gene with haplotype-defining amino acid variants and SNP numbers listed below. Labelled as in a, except the scale indicates 2.5 kbp. (c) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B+/+ and A3B−/− breast tumors with n-values and total mutation numbers in parentheses. C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively. (d) Bar plots depicting the proportions of cytosine mutations occurring in the indicated trinucleotide motifs in A3B−/− breast cancers with the indicated A3H haplotype combinations (n-values and total mutation numbers in parentheses). C-to-T, C-to-G and C-to-A are represented by red, black and blue shading, respectively.
Mentions: To test the hypothesis that stable forms of A3H (haplotypes II, V and VII) contribute to breast cancer mutagenesis in the absence of A3B, we computationally screened and manually confirmed all available breast tumour data sets from TCGA to identify specimens with two copies of the A3B deletion allele, deduce A3H haplotypes and assess association with APOBEC signature mutations (gene schematics in Fig. 1a,b). A total of 17 A3B- tumours were identified and, as reported previously from analyses of 13 -tumours44, the overall APOBEC signature in these tumours is visibly more pronounced than the composite cytosine mutation spectrum from 577 breast tumours with two confirmed intact copies of A3B (boxed in Fig. 1c).

View Article: PubMed Central - PubMed

ABSTRACT

Cytosine mutations within TCA/T motifs are common in cancer. A likely cause is the DNA cytosine deaminase APOBEC3B (A3B). However, A3B- breast tumours still have this mutational bias. Here we show that APOBEC3H haplotype I (A3H-I) provides a likely solution to this paradox. A3B- tumours with this mutational bias have at least one copy of A3H-I despite little genetic linkage between these genes. Although deemed inactive previously, A3H-I has robust activity in biochemical and cellular assays, similar to A3H-II after compensation for lower protein expression levels. Gly105 in A3H-I (versus Arg105 in A3H-II) results in lower protein expression levels and increased nuclear localization, providing a mechanism for accessing genomic DNA. A3H-I also associates with clonal TCA/T-biased mutations in lung adenocarcinoma suggesting this enzyme makes broader contributions to cancer mutagenesis. These studies combine to suggest that A3B and A3H-I, together, explain the bulk of ‘APOBEC signature' mutations in cancer.

No MeSH data available.


Related in: MedlinePlus