High Prevalence of BRCA1 and BRCA2 Germline Mutations With Loss of Heterozygosity In a Series of Resected Pancreatic Adenocarcinoma and Other Neoplastic Lesions

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. 

Experimental Design: This is a single site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish (AJ). DNA from normal pancreatic tissue was genotyped for the three AJ BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT), and loss of heterozygosity (LOH) determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was performed. 

Results: 37 patients underwent surgery for PDAC, 7 for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63, or 19.0%, p<0.001), PDAC cohort (8/37, or 21.6%, p<0.001), and IPMN cohort (2/7 or 28.6%, p=.01) compared to published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%, p<0.001) and BRCA2 6174delT (10.8%, p<0.001) in AJ PDAC patients was demonstrated. BRCA1/2 LOH was found in 2/4 BRCA1-associated PDACs and 3/4 BRCA2-associated PDACs. Positive p53 IHC was found in 5/8 BRCA1/2 PDACs. 

Conclusions: We demonstrate a high prevalence of BRCA1/2 mutations with LOH in an AJ cohort of surgically resected PDAC and neoplastic lesions, suggesting these germline mutations are causal in select individuals.