Identifying Familial Pancreatic Cancer Predisposition Genes

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%，是这种高致死性恶性肿瘤的一个希望领域。在这项提案中，我们计划使用一系列来自多发性胰腺癌家族患者的新胰腺癌细胞系来鉴定患者中遗传的突变基因。我们将使用最近发现另一种导致这种疾病的基因（Palb 2）的相同方法和团队。一旦我们在特定目标1中发现其他基因，我们将在特定目标2中确定它们在96个其他受影响家庭中的患病率。 这项工作对早期发现、遗传咨询和可能的治疗有重要意义，如下：一旦基因已知，我们将能够确定哪些家庭成员需要积极监测以早期发现，哪些只有群体风险。此外，我们将能够就其将疾病传播给后代的风险向家庭提供咨询。最后，家族性胰腺癌的一个已知原因是生殖系BRCA 2基因缺陷，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，或者在现有化疗药物的作用下是合成致死的。假设：FPC生殖系易感性突变解释了大多数FPC。具体目标1：对9种新型FPC细胞系和生殖系DNA进行全基因组测序。分析并收集一系列候选家族易感基因。具体目标2：确认并确定96例FPC患者生殖系样本中易感基因的初始患病率。 公共卫生相关性：2010年，超过95%的胰腺癌患者将在5年内死于该病。其中一个亮点是有可能靶向患者的癌症，这些癌症发生在家庭癌症环境中，因为他们携带两个有缺陷的DNA修复基因拷贝，这是一个致命的弱点。在这项提案中，我们计划发现导致家族性胰腺癌的所有基因，并确定其患病率。

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. PUBLIC HEALTH RELEVANCE: In 2010, more than 95% of pancreatic cancer patients will die of the disease within 5 years. One shining light is the potential to target patient's cancers that arose in a family cancer setting because they bear two defective copies of a DNA repair gene, an Achilles' heel. In this proposal we plan to discover all genes that cause familial pancreatic cancer and determine their prevalence.