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Grant Details

Grant Number: 5R03CA123474-02 Interpret this number
Primary Investigator: Klein, Alison
Organization: Johns Hopkins University
Project Title: BRCA1 and Familial Pancreatic Cancer
Fiscal Year: 2007
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Abstract

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.

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Publications

Elevated cancer mortality in the relatives of patients with pancreatic cancer.
Authors: Wang L, Brune KA, Visvanathan K, Laheru D, Herman J, Wolfgang C, Schulick R, Cameron JL, Goggins M, Hruban RH, Klein AP
Source: Cancer Epidemiol Biomarkers Prev, 2009 Nov;18(11), p. 2829-34.
EPub date: 2009 Oct 20.
PMID: 19843679
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Absence of germline BRCA1 mutations in familial pancreatic cancer patients.
Authors: Axilbund JE, Argani P, Kamiyama M, Palmisano E, Raben M, Borges M, Brune KA, Goggins M, Hruban RH, Klein AP
Source: Cancer Biol Ther, 2009 Jan;8(2), p. 131-5.
EPub date: 2009 Feb 4.
PMID: 19029836
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Incorporating tumor immunohistochemical markers in BRCA1 and BRCA2 carrier prediction.
Authors: Tai YC, Chen S, Parmigiani G, Klein AP
Source: Breast Cancer Res, 2008;10(2), p. 401.
EPub date: 2008 Mar 20.
PMID: 18466632
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