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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.

No MeSH data available.


Related in: MedlinePlus

Models for differential APOBEC mutation accumulation in cancer.The far left column describes the A3B and A3H-I genotypes of each model as well as examples of relevant tumour types. The middle columns show the average mutation rate over time for each model with sources of mutations highlighted in different colours, smoking (blue), A3B (red) and A3H-I (maroon). The far right column depicts the accumulation of somatic APOBEC signature mutations over time, with mutations mediated by A3B and A3H-I represented in red and maroon, respectively. Somatic mutations from both APOBEC3 enzymes are shown as red/maroon diagonal stripes to highlight that these mutations are not easily distinguishable. (a) The continuous mutator model depicts constant A3H-I mediated mutagenesis and subsequent accumulation of APOBEC-signature mutations over time in the absence of A3B as may be occurring in some breast cancers. (b) The activated (early) mutator model depicts a rapid increase in A3B-mediated mutations and APOBEC signature mutations after an A3B-activating event such as HPV-infection in cervical cancers or a currently unknown mechanism in breast cancers. (c) The continuous mutator plus activated (late) mutator model depicts the constant accumulation of APOBEC-signature mutations mediated by A3H-I as shown in a. For contrast, the distinct contribution from smoking-mediated mutagenesis (blue) is shown as an early finite time period. Late activation of A3B then leads to a more rapid accumulation of APOBEC signature mutations over time effectively eclipsing the A3H-I contribution. (d) The activated (late) mutator model is nearly identical to the model shown in c, however the absence of A3H-I results in no early APOBEC-signature mutations as may be occurring in some lung adenocarcinomas.
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f7: Models for differential APOBEC mutation accumulation in cancer.The far left column describes the A3B and A3H-I genotypes of each model as well as examples of relevant tumour types. The middle columns show the average mutation rate over time for each model with sources of mutations highlighted in different colours, smoking (blue), A3B (red) and A3H-I (maroon). The far right column depicts the accumulation of somatic APOBEC signature mutations over time, with mutations mediated by A3B and A3H-I represented in red and maroon, respectively. Somatic mutations from both APOBEC3 enzymes are shown as red/maroon diagonal stripes to highlight that these mutations are not easily distinguishable. (a) The continuous mutator model depicts constant A3H-I mediated mutagenesis and subsequent accumulation of APOBEC-signature mutations over time in the absence of A3B as may be occurring in some breast cancers. (b) The activated (early) mutator model depicts a rapid increase in A3B-mediated mutations and APOBEC signature mutations after an A3B-activating event such as HPV-infection in cervical cancers or a currently unknown mechanism in breast cancers. (c) The continuous mutator plus activated (late) mutator model depicts the constant accumulation of APOBEC-signature mutations mediated by A3H-I as shown in a. For contrast, the distinct contribution from smoking-mediated mutagenesis (blue) is shown as an early finite time period. Late activation of A3B then leads to a more rapid accumulation of APOBEC signature mutations over time effectively eclipsing the A3H-I contribution. (d) The activated (late) mutator model is nearly identical to the model shown in c, however the absence of A3H-I results in no early APOBEC-signature mutations as may be occurring in some lung adenocarcinomas.

Mentions: Our results suggest distinct temporal models for the generation of APOBEC signature mutations in cancer. In the first, in A3B- cancers such as in a subset of breast tumours described here, A3H-I may provide a low mutator activity that over a long period of time results in the observed APOBEC signature mutation spectrum and load (continuous mutator model in Fig. 7a). This mutation programme may be prone to periodic ‘flares' (not depicted) because at least one virus (HIV-1) has been shown to induce A3H expression in primary cells4871, and other viruses may have similar stimulatory effects. This model may be particularly relevant to Southeast Asian populations with high frequencies of both A3H-I and the A3B deletion allele (Fig. 2). In the second model, in A3B overexpressing tumours such as many breast cancers and HPV-positive cancers, the mutational impact of A3B may be early, strong, constitutive and additive to that of A3H-I, and the powerful effect of A3B and its similar TC target preferences may rapidly eclipse the A3H-I contribution (activated (early) mutator model in Fig. 7b). HPV infection provides a mechanism for A3B upregulation in virus-positive tumour types, but the mechanisms responsible for early A3B induction in virus-negative tumours are less uniform and less clear (for example, ref. 26). In the third model, the impact of A3H-I is evident among early-arising clonal mutation spectrum in lung adenocarcinomas but it eventually becomes eclipsed by A3B overexpression at a later point in tumour development (continuous mutator plus activated (late) mutator model in Fig. 7c). In a variant of this model, the early continuous mutator effect is absent in tumours lacking A3H-I (activated (late) mutator model in Fig. 7d). In all of the models, apart from those depicting an early smoking signature, other prominent sources of mutation are excluded for purposes of focusing on the APOBEC signature and the different contributions of A3H-I and A3B observed in this study. Such additional sources of mutation are of course capable of contributing to the overall mutation loads and spectra in various tumour types. These models may extend to APOBEC signature cancers beyond those highlighted here, and future studies should be designed to isolate and quantify the mutagenic contributions of A3H-I, A3B and possibly other family members. Future studies should also examine the clinical impact of these different mutational sources together, as well as in isolation, in appropriate populations. Indeed, an analysis of lung cancer incidence in China indicated that unstable/inactive forms of A3H may be protective72 and, therefore, we suggest that A3H-I could be a significant risk factor as the predominant allele in China (∼70%) and other regions of the world.


The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis
Models for differential APOBEC mutation accumulation in cancer.The far left column describes the A3B and A3H-I genotypes of each model as well as examples of relevant tumour types. The middle columns show the average mutation rate over time for each model with sources of mutations highlighted in different colours, smoking (blue), A3B (red) and A3H-I (maroon). The far right column depicts the accumulation of somatic APOBEC signature mutations over time, with mutations mediated by A3B and A3H-I represented in red and maroon, respectively. Somatic mutations from both APOBEC3 enzymes are shown as red/maroon diagonal stripes to highlight that these mutations are not easily distinguishable. (a) The continuous mutator model depicts constant A3H-I mediated mutagenesis and subsequent accumulation of APOBEC-signature mutations over time in the absence of A3B as may be occurring in some breast cancers. (b) The activated (early) mutator model depicts a rapid increase in A3B-mediated mutations and APOBEC signature mutations after an A3B-activating event such as HPV-infection in cervical cancers or a currently unknown mechanism in breast cancers. (c) The continuous mutator plus activated (late) mutator model depicts the constant accumulation of APOBEC-signature mutations mediated by A3H-I as shown in a. For contrast, the distinct contribution from smoking-mediated mutagenesis (blue) is shown as an early finite time period. Late activation of A3B then leads to a more rapid accumulation of APOBEC signature mutations over time effectively eclipsing the A3H-I contribution. (d) The activated (late) mutator model is nearly identical to the model shown in c, however the absence of A3H-I results in no early APOBEC-signature mutations as may be occurring in some lung adenocarcinomas.
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Related In: Results  -  Collection

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f7: Models for differential APOBEC mutation accumulation in cancer.The far left column describes the A3B and A3H-I genotypes of each model as well as examples of relevant tumour types. The middle columns show the average mutation rate over time for each model with sources of mutations highlighted in different colours, smoking (blue), A3B (red) and A3H-I (maroon). The far right column depicts the accumulation of somatic APOBEC signature mutations over time, with mutations mediated by A3B and A3H-I represented in red and maroon, respectively. Somatic mutations from both APOBEC3 enzymes are shown as red/maroon diagonal stripes to highlight that these mutations are not easily distinguishable. (a) The continuous mutator model depicts constant A3H-I mediated mutagenesis and subsequent accumulation of APOBEC-signature mutations over time in the absence of A3B as may be occurring in some breast cancers. (b) The activated (early) mutator model depicts a rapid increase in A3B-mediated mutations and APOBEC signature mutations after an A3B-activating event such as HPV-infection in cervical cancers or a currently unknown mechanism in breast cancers. (c) The continuous mutator plus activated (late) mutator model depicts the constant accumulation of APOBEC-signature mutations mediated by A3H-I as shown in a. For contrast, the distinct contribution from smoking-mediated mutagenesis (blue) is shown as an early finite time period. Late activation of A3B then leads to a more rapid accumulation of APOBEC signature mutations over time effectively eclipsing the A3H-I contribution. (d) The activated (late) mutator model is nearly identical to the model shown in c, however the absence of A3H-I results in no early APOBEC-signature mutations as may be occurring in some lung adenocarcinomas.
Mentions: Our results suggest distinct temporal models for the generation of APOBEC signature mutations in cancer. In the first, in A3B- cancers such as in a subset of breast tumours described here, A3H-I may provide a low mutator activity that over a long period of time results in the observed APOBEC signature mutation spectrum and load (continuous mutator model in Fig. 7a). This mutation programme may be prone to periodic ‘flares' (not depicted) because at least one virus (HIV-1) has been shown to induce A3H expression in primary cells4871, and other viruses may have similar stimulatory effects. This model may be particularly relevant to Southeast Asian populations with high frequencies of both A3H-I and the A3B deletion allele (Fig. 2). In the second model, in A3B overexpressing tumours such as many breast cancers and HPV-positive cancers, the mutational impact of A3B may be early, strong, constitutive and additive to that of A3H-I, and the powerful effect of A3B and its similar TC target preferences may rapidly eclipse the A3H-I contribution (activated (early) mutator model in Fig. 7b). HPV infection provides a mechanism for A3B upregulation in virus-positive tumour types, but the mechanisms responsible for early A3B induction in virus-negative tumours are less uniform and less clear (for example, ref. 26). In the third model, the impact of A3H-I is evident among early-arising clonal mutation spectrum in lung adenocarcinomas but it eventually becomes eclipsed by A3B overexpression at a later point in tumour development (continuous mutator plus activated (late) mutator model in Fig. 7c). In a variant of this model, the early continuous mutator effect is absent in tumours lacking A3H-I (activated (late) mutator model in Fig. 7d). In all of the models, apart from those depicting an early smoking signature, other prominent sources of mutation are excluded for purposes of focusing on the APOBEC signature and the different contributions of A3H-I and A3B observed in this study. Such additional sources of mutation are of course capable of contributing to the overall mutation loads and spectra in various tumour types. These models may extend to APOBEC signature cancers beyond those highlighted here, and future studies should be designed to isolate and quantify the mutagenic contributions of A3H-I, A3B and possibly other family members. Future studies should also examine the clinical impact of these different mutational sources together, as well as in isolation, in appropriate populations. Indeed, an analysis of lung cancer incidence in China indicated that unstable/inactive forms of A3H may be protective72 and, therefore, we suggest that A3H-I could be a significant risk factor as the predominant allele in China (∼70%) and other regions of the world.

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