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subtypes; new therapeutic target; statistics; symposium; transcriptome; transcriptome sequencing; tumor; tumorigenesis; unpublished works; whole genome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.

项目摘要 抽象的： 狗是人类癌症的公认动物模型，并受赞助商的影响， 最新发作，组织学在组织学上类似于人类组织细胞疾病的恶性组织细胞疾病。犬 组织细胞肉瘤（HS）像人类HS一样极具致命性，虽然在狗品种中很少见，却影响20-25％ 伯尔尼山犬（BMD）和扁平覆盖猎犬（FCR）。全基因组关联研究 表明每个品种中的独特关联，包括BMD中众所周知的癌症基因CDKN2A/B。这 不同易感性局部的表现与疾病表现的差异一致 品种。 FCR的可能性是BMD的两倍，在局部HS中，肿瘤在周围组织中 周围的关节。 BMD开发第二种形式HS的可能性是FCR的七倍 散布或内脏，肿瘤在多个器官中产生。这些离散的关联 临床表现的品种和差异表明，HS的易感性在狗中出现了两次，那里 可能是肿瘤发生的不同机制，从而增加了人类HS研究模型的效用。 所提出的工作的中心假设是HS肿瘤具有通常破坏的基因途径 与肿瘤发生以及HS亚型特异性突变以及与 BMD和FCR中的潜在敏感性机制。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）鉴定体细胞 犬HS肿瘤中的变异和突变特征，以及（3）候选种系的研究 易感性变异和与肿瘤WGS和RNA-Seq数据的结果进行了比较。这个全面 方法将提供与人类疾病相关的新型热靶标和易感性等位基因。 奖学金培训计划： 拟议的工作将在博士博士实验室的国家人类基因组研究所举行。 Elaine Ostrander，犬类遗传学和癌症研究领域的领导者。奖学金培训计划 包括生物信息学，Python，Perl和统计的课程；指导研究生；演讲 在人类遗传学，动物基因组学和癌症会议上；参加NIH讲座系列，期刊俱乐部， 和每周实验室会议；以及赠款写作，工作场所动态和实验室的职业发展课程 管理。具体目标将解决PI的培训目标，该目标将学习概念和 与肿瘤的RNA-Seq和WG相关的技术技能，并提高生物信息学和统计能力 为研究多基因，复杂疾病的犬类遗传学职业准备申请人。