High-throughput sequencing to identify novel melanoma susceptibility genes

高通量测序鉴定新型黑色素瘤易感基因

• 批准号: 8886299
• 负责人: Lisa Cannon Albright
• 金额: $ 109万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886299
• 关键词: Accounting; Affect; Alleles; CDKN2A gene; CHEK2 gene; Candidate Disease Gene; Code; Cutaneous Melanoma; Data; Diagnosis; Disease; Distant; Drops; Early Diagnosis; Epidemiology; European; Family; Family history of; First Degree Relative; Frequencies; Gene Frequency; Generations; Genes; Genetic Risk; Genetic screening method; Genome; Germ-Line Mutation; Goals; Heterozygote; High-Throughput Nucleotide Sequencing; Individual; Joints; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Modeling; Mutate; Mutation; Neoplasm Metastasis; Nucleotides; Pattern; Predisposition; Prevention; Primary Neoplasm; Proteins; Reading; Recruitment Activity; Risk; Risk Factors; Role; Sampling; Skin Carcinoma; Specimen; Staging; Survival Rate; Susceptibility Gene; Testing; United States; Universities; Utah; Validation; Variant; Work; base; carcinogenesis; case control; design; exome; exome sequencing; genetic pedigree; genetic risk factor; genome wide association study; genome-wide; genome-wide linkage; high risk; indexing; insight; malignant breast neoplasm; melanoma; mortality; novel; predictive modeling; public health relevance; rare variant; repository; risk variant; screening; targeted sequencing; tool; treatment strategy; tumor; tumor progression

 DESCRIPTION (provided by applicant): Each year in the United States, over 75,000 individuals are diagnosed with melanoma and over 9,500 individuals die from the disease. When detected early, melanoma is highly curable, with 5-year survival rates of 98% for early stage disease. However, the survival rate drops precipitously for later stages, declining to 62% for regional stages and 16% for distant stages. Advances in the ability to individuals at high risk of developing melanoma in conjunction with improvements in prevention, screening, and early detection have the potential to dramatically reduce disease mortality. In this project, we propose to conduct a hypothesis-free, genome-wide search for novel melanoma-susceptibility genes characterized by rare, protein-coding risk variants. This project builds upon the rich specimen repositories and comprehensive family, epidemiologic, and exposure data at MD Anderson and the University of Utah. There are three specific aims. In Aim 1, we will sequence the whole exomes of 1,200 melanoma cases and 1,200 frequency-matched controls. The cases will include 250 individuals from 125 three- to five-generation high-risk melanoma pedigrees recruited at the University of Utah and 950 familial index cases recruited at MD Anderson with at least one affected first-degree relative. We will perform gene-based tests to identify the top 1,000 candidate genes (p<0.05) using the pedigree Variant Annotation, Analysis & Search Tool (pVAAST), a state-of-the-art method that integrates familial linkage, case- control association, and variant prioritization information in a unified statistical framework. We will also use the off target reads from the exome sequence data to impute single nucleotide variants (SNVs) for each individual across the entire genome. In Aim 2, we will validate the 1,000 candidate genes and top 1,000 SNVs through targeted sequencing in 3,000 melanoma cases and 3,000 controls. Together, Aims 1 and 2 have high power identify novel, intermediate-risk melanoma-susceptibility genes across the entire genome. We will also integrate the genetic risk factors into an existing quantitative melanoma risk prediction model using a subset of 2,000 cases and 1,200 controls for which comprehensive epidemiologic and exposure risk factor data is available. In Aim 3, we will sequence 600 tumors from individuals with damaging rare susceptibility variants identified from Aims 1-2 to test for somatic-germline interaction. The familial and case-control efforts proposed in Aims 1 and 2 are designed to comprehensively identify and then replicate rare genetic risk factors for melanoma on a genome-wide basis. The newly identified risk factors from this study will enable the identification of genetically susceptible individuals at high risk of developing melanoma. The incorporation of somatic variation information will provide additional insight into the role of germline susceptibility varints in cancer progression. The integration of epidemiologic and exposure risk factors will further enhance the translational potential of this work, leading to more effective prevention, early detection, and treatment strategies for this deadly yet often preventable disease.

 描述（由申请人提供）：在美国，每年有超过75，000人被诊断患有黑色素瘤，超过9，500人死于该疾病。当早期发现时，黑色素瘤是高度可治愈的，早期疾病的5年生存率为98%。然而，存活率在后期阶段急剧下降，区域阶段下降到62%，远距离阶段下降到16%。对高危个体的治疗能力的提高 预防、筛查和早期发现的改善有可能大大降低疾病死亡率。在这个项目中，我们建议进行一个无假设的，全基因组搜索新的黑色素瘤易感基因的特点是罕见的，蛋白质编码的风险变异。该项目建立在MD安德森和犹他州大学丰富的标本库和全面的家庭、流行病学和暴露数据的基础上。有三个具体目标。在目标1中，我们将对1，200例黑色素瘤病例和1，200例频率匹配对照的全外显子组进行测序。这些病例将包括来自犹他州大学招募的125个三代至五代高风险黑色素瘤家系的250名个体和来自MD安德森医院招募的950个家族索引病例，其中至少有一名受影响的一级亲属。我们将使用系谱变体注释、分析和搜索工具（pVAAST）进行基于基因的测试以鉴定前1，000个候选基因（p<0.05），pVAAST是一种最先进的方法，其在统一的统计框架中整合了家族连锁、病例对照关联和变体优先化信息。我们还将使用关闭 从外显子组序列数据的靶读段来估算整个基因组中每个个体的单核苷酸变异（SNV）。在目标2中，我们将通过3,000例黑色素瘤病例和3,000例对照的靶向测序来验证1,000个候选基因和前1,000个SNV。目标1和目标2合在一起，具有在整个基因组中识别新型中等风险黑素瘤易感基因的高功效。我们还将整合遗传风险因素， 现有的定量黑色素瘤风险预测模型，使用了2,000例病例和1,200例对照的子集，其综合流行病学和暴露风险因素数据可用。在目标3中，我们将对来自目标1-2中鉴定出的具有破坏性罕见易感性变体的个体的600个肿瘤进行测序，以测试体细胞-种系相互作用。目的1和2中提出的家族和病例对照努力旨在全面识别并在全基因组基础上复制黑色素瘤的罕见遗传风险因素。这项研究中新发现的风险因素将使我们能够识别出患黑色素瘤风险高的遗传易感个体。体细胞变异信息的整合将为生殖系易感性变异在癌症进展中的作用提供额外的见解。流行病学和暴露风险因素的整合将进一步增强这项工作的转化潜力，从而为这种致命但通常可预防的疾病提供更有效的预防，早期发现和治疗策略。