SPONTANEOUS CANINE MODELS FOR CANCER GENE DISCOVERY

用于发现癌症基因的自发犬模型

• 批准号: 7502700
• 负责人: Matthew Breen
• 金额: $ 28.35万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502700
• 关键词: Accounting; Address; Affect; B-Lymphocytes; Behavior; Biological Models; Breeding; Canis familiaris; Case Study; Cessation of life; Chromosomal Gain; Chromosome abnormality; Chromosomes; Classification; Collaborations; Cytogenetic Analysis; Cytogenetics; DNA Sequence; Data; Detection; Diagnosis; Diffuse Lymphoma; Disease; Disease Progression; Environment; Friends; Genes; Genetic; Genetic Heterogeneity; Genetic Predisposition to Disease; Genome; Genomics; Goals; Human; Human Genome; Incidence; Lesion; Location; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Maps; Metaphase; Modeling; Molecular; Molecular Cytogenetics; Morphology; Nature; Numbers; Oncogenes; Patients; Phenotype; Physiology; Population; Predisposition; Prevalence; Recurrence; Relative Risks; Reporting; Research Personnel; Resolution; Resources; Risk; Risk Factors; Role; Sampling; Series; Structure; T-Lymphocyte; Technology; Testing; base; comparative; comparative genomic hybridization; concept; disease natural history; disorder risk; gene discovery; genome wide association study; human study; improved; large cell Diffuse non-Hodgkin' s lymphoma; lifetime risk; lymphoid neoplasm; man; neoplastic cell; outcome forecast; programs; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Project summary. Considerable progress has been made to improve our understanding of the genetic basis of cancer and the mechanisms of oncogenesis. In spite of this, even for widely studied human cancers such as diffuse large B cell lymphoma (DLBCL) causative factors remain elusive. This is due, at least in part, to the extensive genetic heterogeneity of most human populations. In contrast, domestic dogs are organized into more than 350 phenotypically distinct genetic isolates ('breeds') characterized by unique constellations of morphology, behavior, and susceptibility to specific diseases including DLBCL. Humans and dogs share similar physiology, extensive genome homology and are exposed to the same environment. We have shown that the incidence and lifetime risk of naturally occurring canine DLBCL (cDLBCL) differ markedly between breeds and that cytogenetic changes associated with hematopoetic tumors are evolutionary conserved between human and dog. Significantly, we have also identified chromosome aberrations in dogs for which corresponding changes have not yet been reported in humans. Combined with the recent advances in canine genomics resources, these unique features of dog population structure strongly support the role of the dog an ideal model system to identify genes that define diagnosis, prognosis and risk for DLBCL. Using molecular cytogenetics and genome-wide association studies of cDLBCL, we will identify cancer-associated genes that continue to evade detection through comparable studies of human DLBCL. Project relevance: DLBCL is a major cause of human death. Almost 50% of DLBCL patients receiving therapy do not survive more than five years, indicating that the 'disease1 requires further classification and that we need to understand more about the genetic basis of this cancer. We propose that key genes associated with DLBCL continue to remain elusive and undetected in studies of human patients due to the high level of genetic variability in human populations. The structure of purebred dog populations makes them an ideal model for gene discovery. We will investigate chromosome changes associated with canine DLBCL in highly susceptible dog breeds as a means to identify such genes. We propose that Man's best friend will provide the keys to unlocking some of nature's most intriguing puzzles about cancer.

描述(申请人提供)：项目总结。在提高我们对癌症的遗传基础和肿瘤发生机制的理解方面，已经取得了相当大的进展。尽管如此，即使被广泛研究的人类癌症，如弥漫性大B细胞淋巴瘤(DLBCL)，其致病因素仍然难以捉摸。这至少部分归因于大多数人类群体广泛的遗传异质性。相比之下，家犬被组织成350多个表型不同的遗传分离株(‘品种’)，其特征是形态、行为和对包括DLBCL在内的特定疾病的易感性的独特星座。人类和狗有着相似的生理，广泛的基因组同源性，并暴露在相同的环境中。我们已经证明，自然发生的犬DLBCL(CDLBCL)的发病率和终生风险在不同品种之间存在显著差异，与血液肿瘤相关的细胞遗传学变化在人和狗之间是进化保守的。值得注意的是，我们还在狗身上发现了染色体异常，但在人类中尚未报告相应的变化。结合犬基因组学资源的最新进展，犬种群结构的这些独特特征有力地支持了犬的作用，它是识别定义DLBCL诊断、预后和风险的基因的理想模式系统。利用cDLBCL的分子细胞遗传学和全基因组关联研究，我们将通过对人类DLBCL的可比性研究来识别继续逃避检测的癌症相关基因。项目相关性：DLBCL是人类死亡的主要原因。近50%接受治疗的DLBCL患者无法存活超过五年，这表明这种疾病需要进一步分类，我们需要更多地了解这种癌症的遗传基础。我们认为，与DLBCL相关的关键基因在人类患者的研究中仍然是难以捉摸和未被检测到的，因为人类群体中的遗传变异性水平很高。纯种犬的种群结构使其成为基因发现的理想模式。我们将研究与犬类DLBCL相关的染色体变化，以此作为鉴定此类基因的手段。我们认为，人类最好的朋友将提供解开大自然关于癌症的一些最耐人寻味的谜题的钥匙。