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

项目总结 摘要： 狗是一个公认的人类癌症的动物模型，它会受到自发发生的、 晚发型恶性组织细胞疾病，在组织学上与人类组织细胞疾病相似。犬科 组织细胞肉瘤(HS)和人类HS一样，是极其致命的，虽然在不同品种的狗中很少见，但影响20-25% 伯恩山犬(BMD)和平毛猎犬(FCR)。全基因组关联研究 指出每个品种的独特关联，包括BMDS中众所周知的癌症基因CDKN2A/B。这个 不同易感基因座的存在与疾病表现的差异是一致的 品种繁多。FCR发生局限性HS的可能性是BMDS的两倍，关节周围组织有肿瘤 围绕着一个关节。BMD发展成第二种形式HS的可能性是FCR的七倍， 播散性的或内脏的，肿瘤出现在多个器官。这些离散的关联在不相关的 品种和临床表现的差异表明，HS的易感性在狗身上出现了两次，并且 可能是肿瘤发生的不同机制，增加了该模型在人类HS研究中的实用性。这个 拟议工作的中心假设是HS肿瘤具有通常被破坏的基因通路 与肿瘤发生以及HS亚型特异性突变和差异表达谱相关 BMD和FCR的潜在易感机制。以下具体目标将解决这一问题 假设：(1)BMDS和FCRs中HS肿瘤转录组的特征，(2)体细胞的鉴定 犬HS瘤的变异和突变特征，以及(3)候选种系的调查 敏感性变异以及与肿瘤wgs和rna-seq数据结果的比较。这一全面的 该方法将提供与人类疾病相关的新的治疗靶点和易感等位基因。 团契培训计划： 这项拟议的工作将在国家人类基因组研究所的实验室进行。 伊莱恩·奥斯特兰德是犬类遗传学和癌症研究领域的领先者。团契培训计划 包括生物信息学、蟒蛇、perl和统计学课程；研究生辅导；演示文稿。 在人类遗传学、动物基因组学和癌症会议上；出席NIH系列讲座、期刊俱乐部、 和每周的实验室会议；以及关于拨款撰写、工作场所动态和实验室的职业发展课程 管理层。具体目标将涉及PI的培训目标，即学习概念性和 与肿瘤的RNA-SEQ和WGS相关的技术技能，以及提高生物信息学和统计能力 让申请者为研究多基因复杂疾病的犬类遗传学职业做好准备。

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.