Identifying Familial Pancreatic Cancer Predisposition Genes

识别家族性胰腺癌易感基因

• 批准号: 8427329
• 负责人: JAMES R. ESHLEMAN
• 金额: $ 16.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427329
• 关键词: Abbreviations; Accounting; Affect; Area; BRCA2 gene; Cancer Family; Cancer Patient; Cancer cell line; Cause of Death; Collaborations; Counseling; DNA; DNA Repair Gene; DNA repair protein; Defect; Disease; Double Strand Break Repair; Early Diagnosis; Family; Family member; First Degree Relative; Funding; Genes; Genetic Counseling; Goals; Inherited; International; Laboratories; Light; Malignant Neoplasms; Malignant neoplasm of pancreas; Microsatellite Repeats; Mitomycins; Mutation; Pathology; Patients; Pharmaceutical Preparations; Poly(ADP-ribose) Polymerases; Population; Predisposition; Prevalence; Research; Resources; Risk; Sampling; Series; Single Nucleotide Polymorphism; Single-Stranded DNA; Susceptibility Gene; Ursidae Family; Work; cancer cell; cancer genome; genome sequencing; inhibitor/antagonist; mutant; novel; offspring; oncology; pancreatic cancer cells; pancreatic neoplasm; synthetic drug; tumor registry

DESCRIPTION (provided by applicant): Familial Pancreatic Cancer (FPC) accounts for an estimated 5-10% of all pancreatic cancer and is one area of hope in this otherwise highly lethal malignancy. In this proposal, we plan to identify the mutant gene that was inherited in patients using a series of new pancreatic cancer cell lines from patients in families with multiple pancreatic cancers. We will use the same approach and team that recently identified another gene (Palb2) that causes the disease. Once we find additional genes in Specific Aim 1, we will determine their prevalence in 96 additional affected families in Specific Aim 2. The work has important implications for: early detection, genetic counseling and possibly treatment, as follows: Once the gene is known, we will be able to identify which family members need aggressive surveillance for early detection and which have only population risk. Additionally, we will be able to counsel families about their risk of transmitting the disease to their offspring. Finally, one known cause of familial pancreatic cancer is germline BRCA2 gene defects and these cancers are uniquely sensitive to parp inhibitors. It is possible that any new defect will cause similar defects in double strand break repair or will be synthetic lethal with an existing chemotherapeutic drug. Hypothesis: FPC germline predisposition mutations explain the majority of FPC. Specific Aim 1: Perform whole-genome sequencing of 9 novel FPC cell lines and germline DNA. Analyze and assemble a list of candidate familial predisposition genes. Specific Aim 2: Confirm and determine the initial prevalence of the predisposition gene in germline samples from 96 additional patients with FPC.

描述（由申请人提供）：家族性胰腺癌 (FPC) 估计占所有胰腺癌的 5-10%，是这种高度致命的恶性肿瘤的一个希望领域。在这项提案中，我们计划使用来自患有多种胰腺癌家族的患者的一系列新胰腺癌细胞系来鉴定患者遗传的突变基因。我们将使用最近鉴定出导致该疾病的另一种基因（Palb2）的相同方法和团队。一旦我们在具体目标 1 中发现了其他基因，我们将确定其在具体目标 2 中的 96 个其他受影响家庭中的患病率。这项工作对以下方面具有重要意义：早期检测、遗传咨询和可能的治疗，如下所示：一旦知道该基因，我们将能够确定哪些家庭成员需要积极监测以进行早期检测，哪些家庭成员仅具有群体风险。此外，我们将能够向家庭提供有关将疾病传播给后代的风险的咨询。最后，家族性胰腺癌的已知原因之一是种系 BRCA2 基因缺陷，并且这些癌症对 parp 抑制剂特别敏感。任何新的缺陷都有可能在双链断裂修复中引起类似的缺陷，或者对现有的化疗药物来说是合成致死的。假设：FPC 种系易感性突变可以解释大部分 FPC。具体目标 1：对 9 种新型 FPC 细胞系和种系 DNA 进行全基因组测序。分析并组装候选家族易感基因列表。具体目标 2：确认并确定另外 96 名 FPC 患者种系样本中易感基因的初始患病率。