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

• 批准号: 10567006
• 负责人: Jason Sheltzer
• 金额: $ 53.3万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10567006
• 关键词: Affect; Aging; Algorithms; Aneuploidy; Cancer Biology; Cancer cell line; Cells; Chromosomal Gain; Chromosome 1; Chromosome Arm; Chromosome abnormality; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Computing Methodologies; DNA Sequence Alteration; Data; Development; Diploidy; Disease; Dissection; Engineering; Evolution; Frequencies; Genes; Genetic; Genomics; Growth; Hematologic Neoplasms; Human; Human Chromosomes; Individual; KRAS2 gene; Knowledge; Length; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Mutation; Normal tissue morphology; Nucleotides; Oncogenes; Organoids; PIK3CA gene; Patients; Pattern; Phenotype; Physiological; Play; Prevalence; Process; RB1 gene; Recording of previous events; Recurrence; Research; Research Personnel; Role; Sampling; Series; Solid; Techniques; Time; Tissues; Tumor Promotion; Tumor Suppressor Proteins; Work; addiction; arm; arm function; cancer addiction; cancer cell; cancer genome; cancer type; dosage; fitness; genetic approach; genetic manipulation; genetic selection; insight; malignant breast neoplasm; malignant phenotype; mutant; novel; prevent; side effect; theories; therapy design; tool; transcriptomics; treatment strategy; tumor; tumor progression; tumorigenesis

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.

非整倍性是肿瘤基因组的普遍存在但理解不佳的特征。例如，大约25％ 人类癌症的“ Q” 1染色体“ Q”臂的额外副本，使这种扩增更为普遍 在癌症类型的范围内，KRAS，PIK3CA，RB1和许多其他广泛的癌症驱动基因中的突变。 尽管癌症中1q非整倍性的流行率，但我们对其在肿瘤发生中的作用几乎没有深入了解。尽管 进化研究定义了一致的模式，其中单核苷酸取代发生在致癌基因中 和肿瘤补充剂在癌症发育过程中，大多数拷贝数改变的相对时机仍然存在 未知。此外，尽管已经开发了多种方法来实验操纵单一方法 癌症中的基因，我们改变和研究染色体规模剂量变化的能力极为有限。那，我们 缺乏遗传策略，这将使我们能够对非整倍性的方式发展机械理解 CHR1Q获得影响癌症生物学。 我们假设通常观察到诸如CHR1Q-扩增之类的非整倍性可能是癌症 “成瘾”，就像可以将某些癌症添加到Kras和Pik3ca等癌基因的方式一样。 因此，消除这些非整倍性“成瘾”可能会阻止癌症的生长并抑制各种恶性肿瘤 表型。为了调查这一假设，并更广泛地揭示了1Q收入在癌症生物学中的作用， 我们开发了新的计算和功能方法来研究癌症非整倍性。在初步 工作，我们发现CHR1Q收益通常是在 肿瘤发育，我们发现遗传上消除Chr1q非整倍性可防止恶性增长 人类癌。为了基于这些发现，在AIM 1中，我们将优化并采用一种策略来重建 人类肿瘤多样本测序研究的体拷贝数改变的进化时机。 在AIM 2中，我们将采用一种新型的染色体工程方法来消除人类的Chr1q非整倍性 癌症，然后我们将表征非整倍性损害如何影响各种恶性表型。在AIM 3中，我们 将识别在CHR1Q上编码的剂量敏感驱动基因，该基因有助于这种“非整倍成瘾” 表型。总的来说，这些目标将阐明神秘的基因组改变的功能后果 在许多癌症中发现。由于1Q在恶性增长过程中通常会出现1Q，但在正常情况下极为罕见 组织，对这种非整倍性的更多了解可能指出有效的治疗策略 在广泛的肿瘤中，但对正常二倍体组织的影响很小。