SPONTANEOUS CANINE MODELS FOR CANCER GENE DISCOVERY

用于发现癌症基因的自发犬模型

基本信息

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
项目类别：
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&apos s lymphoma lifetime risk lymphoid neoplasm molecular phenotype neoplastic cell outcome forecast programs tumor tumorigenesis

项目摘要

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。在提高我们对癌症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，即使对于广泛研究的人类癌症，例如弥漫性大 B 细胞淋巴瘤 (DLBCL)，其致病因素仍然难以捉摸。这至少部分是由于大多数人群存在广泛的遗传异质性。相比之下，家犬被分为 350 多个表型不同的遗传分离株（“品种”），其特征是独特的形态、行为和对包括 DLBCL 在内的特定疾病的易感性。人类和狗具有相似的生理机能、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不同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类和狗之间是进化保守的。值得注意的是，我们还发现了狗的染色体畸变，而人类尚未报告相应的变化。结合犬基因组学资源的最新进展，狗种群结构的这些独特特征有力地支持了狗作为理想模型系统的作用，以识别定义 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 的可比较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。接受治疗的 DLBCL 患者中几乎 50% 的生存期不会超过五年，这表明这种疾病需要进一步分类，并且我们需要更多地了解这种癌症的遗传基础。我们认为，由于人群中遗传变异性较高，与 DLBCL 相关的关键基因在人类患者的研究中仍然难以捉摸且未被检测到。纯种狗种群的结构使它们成为基因发现的理想模型。我们将研究高度易感犬种中与犬 DLBCL 相关的染色体变化，作为识别此类基因的手段。我们建议人类最好的朋友将提供解开一些有关癌症的自然界最有趣谜题的钥匙。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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。