Molecular origins and impact of APOBEC3 mutagenesis in cancer
APOBEC3 突变的分子起源和对癌症的影响
基本信息
- 批准号:10693177
- 负责人:
- 金额:$ 40.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressB-Cell LymphomasBioinformaticsBiological AssayBiological MarkersBiological ModelsBreast Cancer cell lineCancer EtiologyCancer ModelCancer cell lineCell LineCell modelCellsCharacteristicsClinicalCytidineCytosine deaminaseDataDeaminaseDetectionDimensionsDiseaseEngineeringEnzymesEtiologyEvolutionExposure toFamilyGene MutationGenomeGoalsHigh PrevalenceHumanImmuneIndividualKnock-outLinkLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of urinary bladderMeasuresMetastatic CarcinomaModelingMolecularMonitorMusMutagenesisMutationMutation AnalysisNeoplasm MetastasisOutcomePatient SelectionPatternPhysiologicalPlayPolymeraseProcessRNA VirusesReagentRegulationResistanceRetroelementsRodentRoleSensitivity and SpecificitySingle base substitutionSingle-Stranded DNASiteSourceSurrogate MarkersSystemTestingTherapeuticTransgenesTreatment EfficacyTyrosine Kinase InhibitorXenograft procedurebiomarker validationcancer cellcancer genomecancer preventioncancer therapycancer typecarcinogenesisexperimental studygenome sequencinghuman diseaseimprintinsightlung cancer cellmalignant breast neoplasmmembermutantnovel strategiesoverexpressionparalogous genepreferenceprognosticreconstitutionrecruitscaffoldtargeted treatmenttherapeutic targettherapy resistanttumorigenesiswhole genome
项目摘要
PROJECT SUMMARY
Mutations arise as a result of exogenous and endogenous processes that leave characteristic imprints or
signatures upon the genome. Systematic analysis of these mutational signatures led to the identification of >50
distinct types of single base substitutions (SBS) in human cancer genomes. Revealing the origins of individual
signatures is critical for understanding cancer etiology, with potential implications for cancer prevention and
therapy. Two of the most prevalent mutational signatures in cancer, termed SBS2 and SBS13, are present in
>78% of cancer types and 56% of all cancer genomes, with a particular prominence in breast, bladder, and
lung cancers. SBS2 and SBS13 are proposed to be caused by the endogenous APOBEC3 (A3) enzymes,
which target ssDNA and RNA of viruses and retroelements as part of the innate immune defense. Correlations
between A3 expression, driver gene mutations in A3-preferred contexts, and clinical outcomes suggest that A3
mutagenesis may play important roles in cancer etiology and evolution. Thus, there is strong rationale to
understand the mechanisms of A3 activity. However, reliance on engineered model systems and correlative
data have caused links between A3 enzymes, mutations in cancer, and cancer etiology to be poorly
understood. We have identified human cancer cell lines with endogenous A3 mutagenesis and developed a
workflow that enables us to quantify contributions of individual A3 members to mutations. Here, we propose to
leverage this workflow to accomplish the following goals: 1) Identify A3 mutator enzymes in cancer types where
A3 mutagenesis is prevalent and find biomarkers of their activity; 2) Investigate mechanisms modulating A3
mutagenesis; 3) Determine the functional relevance of A3 mutagenesis in therapy resistance and metastasis.
Aim 1 will expand upon our characterization of human cancer cells with active A3 mutagenesis to identify A3
mutators in breast, bladder, and lung cancers. In parallel, we will directly assess the unknown specificity and
sensitivity of assays to measure activities of individual A3 enzymes. These experiments may further confirm
the speculative A3-etiology of a large number of cancer mutations and quantify contributions of individual A3
enzymes, thus nominating them as putative targets for therapeutic pursuit. Aim 2 builds on our preliminary data
to investigate proposed modulators of A3 mutagenesis. These experiments have the potential to broaden the
scope of therapeutic opportunities focused on cancer cell evolution. Aim 3 will assess the links between A3
enzymes, therapy resistance and metastasis in breast, bladder, and lung cancer cell lines. These experiments
will test predictions from multi-dimensional associations that A3-mutagenesis is a disease-modifying process
that can be therapeutically exploited at various stages of cancer evolution. Taken together, these studies will
define the etiologies of highly prevalent mutational processes and identify strategies to elicit more durable
clinical benefits to targeted therapies and curb metastasis.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN MACIEJOWSKI其他文献
JOHN MACIEJOWSKI的其他文献
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{{ truncateString('JOHN MACIEJOWSKI', 18)}}的其他基金
Immune control and genomic instability at micronuclei
微核的免疫控制和基因组不稳定性
- 批准号:
10365554 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
Immune control and genomic instability at micronuclei
微核的免疫控制和基因组不稳定性
- 批准号:
10544747 - 财政年份:2022
- 资助金额:
$ 40.94万 - 项目类别:
The origins of chromosome rearrangement in the cancer genome
癌症基因组中染色体重排的起源
- 批准号:
9352813 - 财政年份:2016
- 资助金额:
$ 40.94万 - 项目类别:
The origins of chromosome rearrangement in the cancer genome
癌症基因组中染色体重排的起源
- 批准号:
9223946 - 财政年份:2016
- 资助金额:
$ 40.94万 - 项目类别:
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