SPONTANEOUS CANINE MODELS FOR CANCER GENE DISCOVERY

用于发现癌症基因的自发犬模型

• 批准号: 8117247
• 负责人: Matthew Breen
• 金额: $ 27.38万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117247
• 关键词: Accounting; Address; Affect; B-Lymphocytes; Behavior; Biological Models; Breeding; Canis familiaris; Case Study; Cessation of life; Chromosomal Gain; Chromosomal Loss; Chromosome abnormality; Chromosomes; Classification; Collaborations; Cytogenetic Analysis; Cytogenetics; DNA Sequence; Data; Detection; Diagnosis; Disease; Disease Progression; Environment; 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; 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 genomic hybridization; comparative genomics; disease natural history; gene discovery; genome wide association study; improved; large cell Diffuse non-Hodgkin' s lymphoma; lifetime risk; lymphoid neoplasm; molecular phenotype; 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（由申请人提供）：项目摘要。已经取得了相当大的进展，以提高我们对癌症的遗传基础和肿瘤发生机制的理解。尽管如此，即使对于广泛研究的人类癌症如弥漫性大B细胞淋巴瘤（DLBCL），致病因素仍然难以捉摸。这至少部分是由于大多数人类群体的广泛遗传异质性。相比之下，家犬被组织成超过350种表型不同的遗传分离株（“品种”），其特征在于独特的形态、行为和对特定疾病（包括DLBCL）的易感性。人类和狗有着相似的生理机能，广泛的基因组同源性，并且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品种之间存在显着差异，并且与造血肿瘤相关的细胞遗传学变化在人和犬之间是进化保守的。值得注意的是，我们还发现了犬的染色体畸变，而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作为理想模型系统的作用，以鉴定定义DLBCL诊断、预后和风险的基因。利用分子细胞遗传学和cDLBCL的全基因组关联研究，我们将通过对人类DLBCL的可比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。几乎50%接受治疗的DLBCL患者生存时间不超过5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检测到的，因为人类群体中的遗传变异性很高。纯种狗种群的结构使它们成为基因发现的理想模型。我们将调查染色体变化与犬DLBCL在高度易感犬品种作为一种手段，以确定这样的基因。我们认为，人类最好的朋友将提供解开一些自然界最有趣的癌症之谜的钥匙。

项目成果

Update on genomics in veterinary oncology.

• DOI: 10.1053/j.tcam.2009.03.002
• 发表时间: 2009-08
• 期刊: Topics in companion animal medicine
• 影响因子: 1.1
• 作者: Breen M

Refining tumor-associated aneuploidy through 'genomic recoding' of recurrent DNA copy number aberrations in 150 canine non-Hodgkin lymphomas.

• DOI: 10.3109/10428194.2011.559802
• 发表时间: 2011-07
• 期刊: Leukemia & lymphoma
• 影响因子: 2.6
• 作者: Thomas R;Seiser EL;Motsinger-Reif A;Borst L;Valli VE;Kelley K;Suter SE;Argyle D;Burgess K;Bell J;Lindblad-Toh K;Modiano JF;Breen M
• 通讯作者: Breen M

CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies.

• DOI: 10.3109/10428194.2011.654337
• 发表时间: 2012-07
• 期刊: Leukemia & lymphoma
• 影响因子: 2.6
• 作者: Ito D;Frantz AM;Williams C;Thomas R;Burnett RC;Avery AC;Breen M;Mason NJ;O'Brien TD;Modiano JF
• 通讯作者: Modiano JF

Reading between the lines: molecular characterization of five widely used canine lymphoid tumour cell lines.

字里行间：五种广泛使用的犬淋巴肿瘤细胞系的分子特征。

• DOI: 10.1111/j.1476-5829.2011.00299.x
• 发表时间: 2013
• 期刊: Veterinary and comparative oncology
• 影响因子: 2.1
• 作者: Seiser,EL;Thomas,R;Richards,KL;Kelley,MKathryn;Moore,P;Suter,SE;Breen,M
• 通讯作者: Breen,M