Genomic Approaches to Defining Inherited Basis of Childhood Cancer

定义儿童癌症遗传基础的基因组方法

• 批准号: 7988476
• 负责人: Sharon E. Plon
• 金额: $ 62.72万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988476
• 关键词: Adult; Affect; Age; Alleles; Bioinformatics; Cancer Detection; Cancer Etiology; Cancer Family; Cancer Patient; Cancer-Predisposing Gene; Candidate Disease Gene; Cell Line; Child; Childhood; Clinical; Code; Constitutional; Copy Number Polymorphism; DNA; DNA Resequencing; DNA Sequence Rearrangement; Data; Deletion Mutation; Developmental Delay Disorders; Enrollment; Evaluation; Evolution; Exons; Family; Family history of; Family member; Gene Deletion; General Population; Generations; Genes; Genetic Predisposition to Disease; Genetic Programming; Genome; Genomics; Goals; Health Sciences; Human Genome; Inherited; Knowledge; Libraries; Malignant Childhood Neoplasm; Malignant Neoplasms; Medical; Medicine; Methodology; Missense Mutation; Modeling; Molecular; Mutation; National Cancer Institute; Oncogenes; Patients; Pattern; Pediatric Hospitals; Phenotype; Philadelphia; Population Heterogeneity; Predisposition; Prevention approach; Probability; RNA Splicing; Rice; Risk; Sampling; Second Primary Neoplasms; Sequence Analysis; Site; Solid; Somatic Mutation; Specimen; Statistical Methods; Strategic Planning; Syndrome; Technology; Texas; Tumor Suppressor Genes; Tumor Tissue; Universities; University of Texas M D Anderson Cancer Center; Variant; base; cancer genetics; cancer risk; clinical application; clinically relevant; cohort; exome; genome sequencing; genome wide association study; immortalized cell; improved; insight; next generation; novel; proband; public health relevance; sarcoma; statistics; therapeutic target; tumor

DESCRIPTION (provided by applicant): Identification of mutations in specific genes responsible for cancer susceptibility impacts decisions about treatment of the patient as well as allowing increased surveillance and prevention approaches for at-risk family members. In addition, knowledge of inherited predisposition to pediatric malignancies has provided important insights into the mechanisms of cancer and potential therapeutic targets in both children and adults with cancer in the general population. Current utilization of high-throughput sequencing methodologies for coding changes has been focused on somatic mutations in tumor tissue, and conversely; genome-wide association studies of cancer susceptibility have focused on common variations that individually have small impacts on cancer risk. We propose a project at the intersection of these two different approaches. We plan to use massively parallel sequence analyses of constitutional DNA from childhood cancer patients with medical and family history suggestive of a cancer susceptibility syndrome. In Aim 1 we will focus on cohorts of families with consistent and specific phenotypes, for example, probands with childhood sarcomas and second malignancies by age 40 where thorough analysis of well-characterized cancer-associated genes has been negative. The molecular analyses of germline DNA will include two comprehensive approaches (1) capture of all coding exons followed by sequencing at dense coverage to identify mutations pathogenic mutations (deletion, nonsense, frameshift or splice site) that impact coding sequence (whole exome) and (2) whole genome sequencing of paired-ends libraries at lower coverage to identify copy number changes and novel rearrangements. In Aim 2, we will carry out informative statistical and bioinformatics analysis of rare or novel missense alleles, using original methodology involving optimization of alignment depths for evolution-based studies of functionality. In Aim 3, analyses of copy number change and rearrangement by whole genome sequencing will include an additional cohort of subjects with childhood cancer and congenital anomalies or developmental delay to uncover novel contiguous gene or rearrangement syndromes. Results from these initial cohorts will then be validated by targeted sequencing of implicated genes in additional childhood cancer probands and families. To complete this translational, cross-disciplinary project we include collaborators from pediatric cancer genetics programs at Texas Children's Hospital, University of Texas MD Anderson Cancer Center and Health Science Center at San Antonio and the Children's Hospital of Philadelphia, the Human Genome Sequencing Center and the Department of Statistics at Rice University. The clinical centers enroll families from ethnically diverse populations with linkage to medical data, and establishment of immortalized cell lines to facilitate the generation of functionally and clinically relevant data. Our plan to thoroughly interrogate the constitutional genome will advance the goals of the National Cancer Institute's Strategic Plan on gaining a fuller understanding of the spectrum of genetic susceptibility to cancer in highly affected childhood cancer families. PUBLIC HEALTH RELEVANCE: Identification of mutations cancer susceptibility genes impacts decisions about treatment of the patient as well as allowing increased surveillance and prevention approaches for at-risk family members. We plan to use massively parallel sequence analyses of all coding regions in constitutional DNA from childhood cancer patients with medical and family history suggestive of a cancer susceptibility syndrome to identify novel cancer susceptibility genes and gain a fuller understanding of the spectrum of genetic susceptibility to cancer.

描述（由申请人提供）：鉴定负责癌症敏感性的特定基因中突变会影响有关患者治疗的决策，并允许增加监视和预防高危家族的方法。此外，对小儿恶性肿瘤的遗传易感性的了解为一般人群中儿童和成人的癌症和潜在治疗靶点的机制提供了重要的见解。当前利用高通量测序方法用于编码变化的方法已集中在肿瘤组织中的体细胞突变上，相反。全基因组易感性研究的研究集中在对癌症风险影响较小的常见变异上。我们在这两种不同方法的交集中提出了一个项目。我们计划使用医学和家族病史的儿童癌症患者的宪法DNA进行大规模平行的序列分析，这表明癌症易感性综合征。在AIM 1中，我们将专注于具有一致和特定表型的家族的人群，例如，到40岁时患有儿童肉瘤和第二次恶性肿瘤的概率，对特征良好的癌症相关基因的彻底分析为阴性。种系DNA的分子分析将包括两种全面的方法（1）捕获所有编码外显子，然后在致密覆盖范围内进行测序，以鉴定突变的致病突变（删除，胡说八道，毫无意义，移码或剪接站点），以影响编码序列（整个Exome）和（2）整个基因组测序的整个基因组测序，以识别覆盖物的整个基因组测序，以识别覆盖范围的整个基因组测序。在AIM 2中，我们将使用涉及对基于进化的功能研究的优化对齐深度进行优化的原始方法，对稀有或新颖的错位等位基因进行信息丰富的统计和生物信息学分析。在AIM 3中，通过整个基因组测序对拷贝数变化和重排的分析将包括其他患有儿童癌症和先天异常的受试者或发育延迟，以发现新的连续基因或重排综合症。然后，这些初始人群的结果将通过对其他儿童癌症概率和家庭中涉及的基因进行靶向测序来验证。 为了完成这一翻译，跨学科项目，我们包括来自德克萨斯儿童医院，得克萨斯大学医学博士安德森癌症中心和圣安东尼奥的健康科学中心的儿科癌症遗传学计划的合作者，以及费城儿童医院，人类基因组测序中心以及赖斯大学的统计局。临床中心招募了来自种族多样化人群的家庭，并与医学数据联系在一起，并建立了永生的细胞系，以促进在功能和临床上相关的数据的产生。我们彻底询问宪法基因组的计划将促进国家癌症研究所的战略计划的目标，即在受影响的儿童癌症家庭中对遗传易感性的频谱有更深入的了解。 公共卫生相关性：鉴定癌症易感性基因的鉴定会影响有关患者治疗的决策，并允许增加监视和预防高危家庭成员的方法。我们计划在儿童癌症患者和家族史的儿童癌症患者中使用所有编码区域的大规模平行序列分析，暗示癌症易感性综合征，以鉴定新的癌症敏感性基因，并对遗传易感性癌症的易感性谱。