Simultaneous identification of germline and somatic mutations associated with histiocytic sarcoma in a canine model

在犬模型中同时鉴定与组织细胞肉瘤相关的种系和体细胞突变

• 批准号: 9793952
• 负责人: Jacquelyn Evans
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9793952
• 关键词: 17p13.1; 8 year old; Accounting; Address; Affect; Aggressive behavior; Alleles; Animal Model; Animals; Architecture; Bioinformatics; Biological; Biological Process; Blood; CDKN2A gene; Canis familiaris; Catalogs; Chromosomes; Clinical; Complex; Coupled; DNA; DNA Sequence Rearrangement; Data; Data Set; Development; Disease; Etiology; Expression Profiling; Fellowship; Gene Expression; Gene Fusion; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Transcription; Genetic study; Genomics; Germ-Line Mutation; Goals; Grant; Histiocytic sarcoma; Histologic; Human; Human Genetics; Individual; Investigation; Joints; Journals; Laboratories; Learning; Life; Limb structure; Liver; Location; Lung; Malignant Histiocytic Disorders; Malignant Neoplasms; Mentors; Modeling; Molecular; Mutation; National Human Genome Research Institute; Nature; Oncogenes; Organ; Pathway interactions; Pattern; Predisposition; Publishing; Pythons; RNA; Research; Risk; Sampling; Series; Somatic Mutation; Spleen; Susceptibility Gene; Technical Expertise; Therapeutic; Time; Tissues; Training; Transcript; United States National Institutes of Health; Variant; Visceral; Work; Workplace; Writing; anticancer research; cancer genome; career; career development; causal variant; course development; differential expression; dog genome; genetic architecture; genome sequencing; genome wide association study; genome-wide; graduate student; histiocyte; human disease; human model; improved; lectures; meetings; molecular subtypes; new therapeutic target; statistics; symposium; transcriptome; transcriptome sequencing; tumor; tumorigenesis; unpublished works; whole genome

PROJECT SUMMARY Abstract: Dogs are a well-established animal model for human cancers and are affected by a spontaneously occurring, late onset, malignant histiocytic disorder that is histologically similar to human histiocytic disease. Canine histiocytic sarcoma (HS), like human HS, is extremely lethal, and while rare across dog breeds affects 20-25% of Bernese Mountain Dogs (BMDs) and Flat-coated Retrievers (FCRs). Genome-wide association studies indicate unique associations in each breed, including the well-known cancer gene CDKN2A/B in BMDs. The presence of distinct susceptibility loci is consistent with differences in disease presentation between the breeds. FCRs are twice as likely as BMDs to develop localized HS, with a tumor in the periarticular tissue surrounding a joint. BMDs are seven times more likely than FCRs to develop the second form of HS, disseminated or visceral, with tumors arising in multiple organs. These discrete associations in the unrelated breeds and differences in clinical presentation suggest that predisposition to HS arose twice in dogs, and there may be distinct mechanisms of tumorigenesis, increasing the utility of the model for human HS studies. The central hypothesis of the proposed work is that HS tumors possess commonly disrupted gene pathways related to tumorigenesis as well as HS subtype-specific mutations and differential expression profiles related to the underlying susceptibility mechanisms in BMDs and FCRs. The following specific aims will address this hypothesis: (1) characterization of the HS tumor transcriptome in BMDs and FCRs, (2) identification of somatic variation and mutational signatures in canine HS tumors, and (3) investigation of germline candidate susceptibility variants and comparison to results from tumor WGS and RNA-seq data. This comprehensive approach will provide novel therapeutic targets and susceptibility alleles of relevance to human disease. Fellowship Training Plan: The proposed work will take place at the National Human Genome Research Institute in the laboratory of Dr. Elaine Ostrander, a leader in the field of canine genetics and cancer research. The fellowship training plan includes courses in bioinformatics, python, Perl, and statistics; mentoring of a graduate student; presentations at human genetics, animal genomics, and cancer conferences; attendance at NIH lecture series, journal clubs, and weekly lab meetings; and career development courses in grant writing, workplace dynamics, and lab management. The specific aims will address the PI’s training goals, which are to learn conceptual and technical skills related to RNA-seq and WGS of tumors and to improve bioinformatics and statistical abilities to prepare the applicant for a career in canine genetics studying multigenic, complex disease.

项目概要 抽象的： 狗是一种成熟的人类癌症动物模型，并受到自发发生的癌症的影响， 迟发性恶性组织细胞疾病，组织学上与人类犬组织细胞疾病相似。 组织细胞肉瘤 (HS) 与人类 HS 一样，具有极高的致命性，虽然在犬类中很少见，但影响 20-25% 伯恩山犬（BMD）和平毛寻回犬（FCR）的全基因组关联研究。 表明每个品种都有独特的关联，包括 BMD 中众所周知的癌症基因 CDKN2A/B。 不同易感位点的存在与不同人群之间疾病表现的差异是一致的 FCR 品种发生局部 HS（关节周围组织有肿瘤）的可能性是 BMD 品种的两倍。 围绕关节的 BMD 发生第二种形式 HS 的可能性是 FCR 的七倍， 播散性或内脏性，肿瘤出现在多个不相关的器官中。 品种和临床表现的差异表明，狗的 HS 易感性出现两次，并且 可能是不同的肿瘤发生机制，增加了该模型在人类 HS 研究中的实用性。 这项工作的中心假设是 HS 肿瘤通常具有被破坏的基因通路 与肿瘤发生相关以及 HS 亚型特异性突变和差异表达谱相关 BMD 和 FCR 的潜在敏感性机制 以下具体目标将解决这个问题。 假设：(1) BMD 和 FCR 中 HS 肿瘤转录组的表征，(2) 体细胞的鉴定 犬 HS 肿瘤的变异和突变特征，以及 (3) 种系候选者的研究 敏感性变异以及与肿瘤 WGS 和 RNA-seq 数据结果的比较。 该方法将提供与人类疾病相关的新治疗靶点和易感性等位基因。 奖学金培训计划： 拟议的工作将在国家人类基因组研究所的博士实验室进行。 伊莱恩·奥斯特兰德 (Elaine Ostrander)，犬类遗传学和癌症研究领域的领导者。 包括生物信息学、Python、Perl 和研究生演讲的指导； 参加人类遗传学、动物基因组学和癌症会议；参加 NIH 讲座系列、期刊俱乐部、 每周实验室会议；以及资助写作、工作场所动态和实验室的职业发展课程 具体目标将涉及 PI 的培训目标，即学习概念和知识。 与肿瘤RNA-seq和WGS相关的技术技能，并提高生物信息学和统计能力 为申请人从事犬类遗传学研究多基因、复杂疾病的职业做好准备。