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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 contributes APOBEC signature mutations to lung cancer.(a) Tree-based cartoon of tumour evolution. To represent the heterogeneity of each tumour deep sequencing data set (boxed area), 1 trunk mutation (blue) and 3 branch mutations (other colours) are depicted on a background of normal germline DNA (grey). Trunk mutations occur early and are found in every tumour branch, whereas branch mutations occur later in one or more branches (that is, clonal versus subclonal). (b) Bar plots showing the frequency of clonal and subclonal mutations in the indicated cancer types attributable to APOBEC, smoking and ageing (BRCA, breast cancer; CESC, cervical cancer; LUAD, lung adenocarcinoma). Each bar represents the average proportion ±SEM of signature mutations occurring within each A3H haplotype group (that is, A3H-I versus non-A3H-I). The total number of tumours with 1 or 2 copies of G105 (A3H-I) or 2 copies of R105 (A3H-II and other haplotypes) is indicated within the first set of histogram bars. Welch's two-tailed t-test for each category was used to calculate the P value above each graph.
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f6: A3H haplotype I contributes APOBEC signature mutations to lung cancer.(a) Tree-based cartoon of tumour evolution. To represent the heterogeneity of each tumour deep sequencing data set (boxed area), 1 trunk mutation (blue) and 3 branch mutations (other colours) are depicted on a background of normal germline DNA (grey). Trunk mutations occur early and are found in every tumour branch, whereas branch mutations occur later in one or more branches (that is, clonal versus subclonal). (b) Bar plots showing the frequency of clonal and subclonal mutations in the indicated cancer types attributable to APOBEC, smoking and ageing (BRCA, breast cancer; CESC, cervical cancer; LUAD, lung adenocarcinoma). Each bar represents the average proportion ±SEM of signature mutations occurring within each A3H haplotype group (that is, A3H-I versus non-A3H-I). The total number of tumours with 1 or 2 copies of G105 (A3H-I) or 2 copies of R105 (A3H-II and other haplotypes) is indicated within the first set of histogram bars. Welch's two-tailed t-test for each category was used to calculate the P value above each graph.

Mentions: Given the results detailed above, particularly the potent enzymatic activity of A3H-I with an intrinsic preference for cytosines in a TC context, the capacity of A3H-I to mutate a variety of substrates, and the ability of A3H-I to breach the nuclear compartment, we next performed a comprehensive analysis of all available TCGA tumour data sets with n-values >400 exomes to begin to assess whether A3H-I is a general source of mutation in cancer or a unique mechanism that compensates for the loss of A3B in a limited subset of breast cancers. To distinguish between these possibilities, we determined whether A3H-I associates with common mutation signatures including APOBEC, smoking and ageing (respectively, C-to-T in TCW motifs, C-to-A in any motif and C-to-T in CG motifs). We predicted an association of A3H-I with APOBEC signature in some tumour types, but not with smoking or ageing in any tumour type because these signatures are clearly due to independent mechanisms. Mutations with the highest frequency of occurrence in a given tumour normalized by copy number and tumour purity are considered early arising and clonal, whereas any mutation occurring at a lower frequency is considered later-arising and subclonal (Fig. 6a). Such temporal relationships are critical because different mutational processes have been shown to promote different stages of tumour evolution3.


The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
A3H haplotype I contributes APOBEC signature mutations to lung cancer.(a) Tree-based cartoon of tumour evolution. To represent the heterogeneity of each tumour deep sequencing data set (boxed area), 1 trunk mutation (blue) and 3 branch mutations (other colours) are depicted on a background of normal germline DNA (grey). Trunk mutations occur early and are found in every tumour branch, whereas branch mutations occur later in one or more branches (that is, clonal versus subclonal). (b) Bar plots showing the frequency of clonal and subclonal mutations in the indicated cancer types attributable to APOBEC, smoking and ageing (BRCA, breast cancer; CESC, cervical cancer; LUAD, lung adenocarcinoma). Each bar represents the average proportion ±SEM of signature mutations occurring within each A3H haplotype group (that is, A3H-I versus non-A3H-I). The total number of tumours with 1 or 2 copies of G105 (A3H-I) or 2 copies of R105 (A3H-II and other haplotypes) is indicated within the first set of histogram bars. Welch's two-tailed t-test for each category was used to calculate the P value above each graph.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036005&req=5

f6: A3H haplotype I contributes APOBEC signature mutations to lung cancer.(a) Tree-based cartoon of tumour evolution. To represent the heterogeneity of each tumour deep sequencing data set (boxed area), 1 trunk mutation (blue) and 3 branch mutations (other colours) are depicted on a background of normal germline DNA (grey). Trunk mutations occur early and are found in every tumour branch, whereas branch mutations occur later in one or more branches (that is, clonal versus subclonal). (b) Bar plots showing the frequency of clonal and subclonal mutations in the indicated cancer types attributable to APOBEC, smoking and ageing (BRCA, breast cancer; CESC, cervical cancer; LUAD, lung adenocarcinoma). Each bar represents the average proportion ±SEM of signature mutations occurring within each A3H haplotype group (that is, A3H-I versus non-A3H-I). The total number of tumours with 1 or 2 copies of G105 (A3H-I) or 2 copies of R105 (A3H-II and other haplotypes) is indicated within the first set of histogram bars. Welch's two-tailed t-test for each category was used to calculate the P value above each graph.
Mentions: Given the results detailed above, particularly the potent enzymatic activity of A3H-I with an intrinsic preference for cytosines in a TC context, the capacity of A3H-I to mutate a variety of substrates, and the ability of A3H-I to breach the nuclear compartment, we next performed a comprehensive analysis of all available TCGA tumour data sets with n-values >400 exomes to begin to assess whether A3H-I is a general source of mutation in cancer or a unique mechanism that compensates for the loss of A3B in a limited subset of breast cancers. To distinguish between these possibilities, we determined whether A3H-I associates with common mutation signatures including APOBEC, smoking and ageing (respectively, C-to-T in TCW motifs, C-to-A in any motif and C-to-T in CG motifs). We predicted an association of A3H-I with APOBEC signature in some tumour types, but not with smoking or ageing in any tumour type because these signatures are clearly due to independent mechanisms. Mutations with the highest frequency of occurrence in a given tumour normalized by copy number and tumour purity are considered early arising and clonal, whereas any mutation occurring at a lower frequency is considered later-arising and subclonal (Fig. 6a). Such temporal relationships are critical because different mutational processes have been shown to promote different stages of tumour evolution3.

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