Genomic and functional approaches to characterize Chr1q gains in cancer

表征癌症中 Chr1q 增益的基因组和功能方法

基本信息

  • 批准号:
    10567006
  • 负责人:
  • 金额:
    $ 53.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-18 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

Aneuploidy is a ubiquitous but poorly-understood feature of tumor genomes. For instance, approximately 25% of human cancers harbor extra copies of the “q” arm of chromosome 1, making this amplification more common across cancer types than mutations in KRAS, PIK3CA, RB1, and many other widely-studied cancer driver genes. Despite the prevalence of 1q aneuploidy in cancer, we have little insight into its role in tumorigenesis. While evolutionary studies have defined consistent patterns in which single nucleotide substitutions occur in oncogenes and tumor suppressors during cancer development, the relative timing of most copy number alterations remains unknown. Additionally, while multiple approaches have been developed to experimentally manipulate single genes in cancer, our ability to alter and study chromosome-scale dosage changes is extremely limited. Thus, we lack genetic strategies that would allow us to develop a mechanistic understanding of how aneuploidies like Chr1q gains influence cancer biology. We hypothesize that certain commonly observed aneuploidies like Chr1q-amplifications may function as cancer “addictions”, in the same way that some cancers can be addicted to oncogenes like KRAS and PIK3CA. Eliminating these aneuploidy “addictions” could therefore block cancer growth and suppress various malignant phenotypes. To investigate this hypothesis, and to uncover the role of 1q-gains in cancer biology more broadly, we have developed novel computational and functional approaches to study cancer aneuploidy. In preliminary work, we discovered that Chr1q gains are commonly the first arm-scale copy number change that occurs during tumor development, and we found that genetically eliminating Chr1q aneuploidy prevents malignant growth in human cancers. To build on these findings, in Aim 1, we will optimize and apply a strategy to reconstruct the evolutionary timing of somatic copy number alterations from multi-sample sequencing studies of human tumors. In Aim 2, we will apply a novel chromosome-engineering approach to eliminate Chr1q aneuploidy from human cancers, and then we will characterize how aneuploidy-loss affects various malignant phenotypes. In Aim 3, we will identify the dosage-sensitive driver genes encoded on Chr1q that contribute to this “aneuploidy addiction” phenotype. In total, these aims will shed light on the functional consequences of an enigmatic genomic alteration found in many cancers. As 1q gains commonly arise during malignant growth but are extremely rare in normal tissue, a greater understanding of this aneuploidy could point toward treatment strategies that are effective against a wide range of tumors but that have little effect on normal diploid tissue.
非整倍体是肿瘤基因组中普遍存在但却鲜为人知的特征。例如,大约25%

项目成果

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Jason Sheltzer其他文献

Jason Sheltzer的其他文献

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{{ truncateString('Jason Sheltzer', 18)}}的其他基金

FASEB SRC: The Consequences of Aneuploidy: Honoring the Contributions of Angelika Amon
FASEB SRC:非整倍体的后果:纪念 Angelika Amon 的贡献
  • 批准号:
    10467260
  • 财政年份:
    2022
  • 资助金额:
    $ 53.3万
  • 项目类别:
Discovering the mechanisms of-action-mistargeted anti-cancer agents
发现错误靶向抗癌药物的作用机制
  • 批准号:
    10390462
  • 财政年份:
    2020
  • 资助金额:
    $ 53.3万
  • 项目类别:
Discovering the mechanisms of-action-mistargeted anti-cancer agents
发现错误靶向抗癌药物的作用机制
  • 批准号:
    10533110
  • 财政年份:
    2020
  • 资助金额:
    $ 53.3万
  • 项目类别:
Discovering the mechanisms of-action-mistargeted anti-cancer agents
发现错误靶向抗癌药物的作用机制
  • 批准号:
    10759016
  • 财政年份:
    2020
  • 资助金额:
    $ 53.3万
  • 项目类别:
Discovering the mechanisms of-action-mistargeted anti-cancer agents
发现错误靶向抗癌药物的作用机制
  • 批准号:
    10668942
  • 财政年份:
    2020
  • 资助金额:
    $ 53.3万
  • 项目类别:
Discovering the mechanisms-of-action of mistargeted anti-cancer agents
发现错误靶向抗癌药物的作用机制
  • 批准号:
    9886861
  • 财政年份:
    2020
  • 资助金额:
    $ 53.3万
  • 项目类别:
Identification and characterization of genomic features affecting survival duration in cancer
影响癌症生存期的基因组特征的鉴定和表征
  • 批准号:
    9146424
  • 财政年份:
    2015
  • 资助金额:
    $ 53.3万
  • 项目类别:
Identification and characterization of genomic features affecting survival duration in cancer
影响癌症生存期的基因组特征的鉴定和表征
  • 批准号:
    10063482
  • 财政年份:
    2015
  • 资助金额:
    $ 53.3万
  • 项目类别:

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