BRCA1 and Familial Pancreatic Cancer

描述(申请人提供)：胰腺癌是美国癌症死亡的第四大原因。BRCA2基因的遗传突变占家族性胰腺癌病例的1/6，明显散发性胰腺癌病例的1/14。BRCA2蛋白是Fanconi贫血DNA修复途径的一部分。Fanconi缺陷细胞系对DNA交联剂丝裂霉素C和顺铂(程度较小)过敏。临床研究正在进行中，以评估因遗传途径缺陷而产生的癌症患者是否从这些交联剂的靶向治疗中受益。BRCA1蛋白最近被证明是这一相同途径的一部分。然而，遗传性BRCA1基因突变与胰腺癌之间的关联尚不清楚。一些针对高危乳腺癌家族的研究报告称，BRCA1携带者患胰腺癌的风险显著增加。然而，这些研究并不是为了解决“遗传性BRCA1基因突变是否会增加家族性胰腺癌风险”的问题。因此，这项拟议的研究的主要目标是确定遗传性BRCA1基因突变在家族性胰腺癌患者中的流行率。这项研究将利用研究家族性胰腺癌的独特资源--约翰霍普金斯大学的国家家族性胰腺肿瘤登记处。我们将采取双管齐下的方法来解决这个问题。首先，将对来自至少有三例胰腺癌患者家族的胰腺癌患者进行BRCA1基因的全序列分析。其次，我们将检查从胰腺癌家族成员的个体手术切除的浸润性乳腺癌的组织学，以确定这些癌症的形态和免疫组织化学标记模式是否与BRCA1缺陷乳腺癌的报道模式一致。如果与BRCA1缺陷性肿瘤一致，我们将对一个胰腺癌家族成员进行BRCA1基因的完整序列分析。如果BRCA1基因的遗传突变被证明在胰腺癌的发展中起着重要作用，这将对这些胰腺癌患者及其家人的治疗、筛查和遗传咨询产生实质性影响。

DESCRIPTION (provided by applicant): Pancreatic cancer is the 4th leading cause of cancer death in the United States. Inherited mutations in the BRCA2 gene account for 1 in 6 cases of familial pancreatic cancer cases and 1 in 14 cases of apparently sporadic pancreatic cancer. The BRCA2 protein functions as part of the Fanconi Anemia DNA repair pathway. Fanconi defective cell lines are hypersensitive to the DNA crosslinking agent mitomycin C and to a lesser extent cis-platin. Clinical studies to assess if patients with cancers arising because of inherited defects in the pathway benefit from targeted treatment with these crosslinking agents are underway. The BRCA1 protein has been recently shown to be part of this same pathway. However, the association between inherited BRCA1 gene mutations and pancreatic cancer is unclear. A few studies of high-risk breast cancer families have reported a significantly increased risk of pancreatic cancer among BRCA1 carriers. However, these studies were not designed to address the question of "do inherited BRCA1 gene mutations increase the risk of familial pancreatic cancer". Therefore, the primary goal of this proposed study is to determine the prevalance of inherited BRCA1 gene mutations in patients with familial pancreatic cancer. This study will take advantage of a unique resource for the study of familial pancreatic cancer - the National Familial Pancreas Tumor Registry at Johns Hopkins. We will take a two-pronged approach to address this question. First, full sequence analysis of the BRCA1 gene will be performed on pancreatic cancer patients from families in which there are at least three cases of pancreatic cancer. Secondly, we will examine the histology of invasive breast carcinomas surgically resected from individuals with a family member with pancreatic cancer to determine if the morphology and immunohistochemical labeling pattern of these carcinomas is consistent with the patterns reported in BRCA1 deficient breast carcinomas. If consistent with BRCA1 deficient tumors we will then perform complete sequence analysis of the BRCA1 gene on a family member with pancreatic cancer. If inherited mutations in the BRCA1 gene are shown to play a significant role in the development of pancreatic cancer, this will have a substantial impact on the treatment, screening and genetic counseling of these pancreatic cancer patients and their family members.