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. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. Results Thirty-seven patients underwent surgery for PDAC, seven 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; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P =.01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. Conclusions We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.

Incidence and Trends of Malignant and Benign Pancreatic Lesions in Yazd, Iran between 2001 and 2011

“…Another contributing factor, cigarette smoking has proven epidemiological correlation with development of pancreatic cancer (Momi (Schenk et al, 2001), type 2 diabetes mellitus, (Huxley et al, 2005) and an abundance of single genetic mutations, genetic loci, and hereditary syndromes (Iacobuzio-Donahue, 2012;Klein, 2012;McWilliams et al, 2011). Hereditary conditions including among others familial breast cancer with BRCA2 mutation (Lucas et al, 2013), Peutz-Jeghers syndrome (van Lier et al, 2010), and Hereditary Nonpolyposis Colorectal Cancer (HNCC) (Holmes and Bordeianou, 2011) have been causally implicated in malignant tumors of the pancreas. Genetic predisposition is believed to account for 10% of all cases of the disease (Kimmey et al, 2002).…”

Pancreatic ductal adenocarcinoma in BRCA2 mutation carriers

“…Patients with BRCA2-associated PDAC are younger than their counterparts with sporadic PDAC, with a median age difference of 7 years (63 vs 70 years, respectively) in two large studies, but a similar sex ratio (Kim et al 2009, Lucas et al 2013. Other clinicopathological features were similar in both populations except for a personal and family history of cancer (Ferrone et al 2008, Golan et al 2014).…”

“…However, all BRCA2-related PDAC families are not affected with a family history of breast, ovarian and/or prostate cancers, and PDAC can result as the single family cancer in some families with BRCA2 germline mutations, suggesting variable penetrance and phenotypic expression (Goggins et al 1996, Couch et al 2007, Klein 2012, Zhen et al 2015. Germline BRCA2 mutations, particularly the founder 6174delT mutation, are associated with 10-20% of unselected and apparently sporadic PDAC in the Jewish Ashkenazi population (Ozçelik et al 1997, Ferrone et al 2008, Lucas et al 2013.…”

“…In 2012, the International Cancer of the Pancreas Screening (CAPS) Consortium published guidelines on the management of patients with increased risk for familial PDAC (Canto et al 2013). The aim of screening is to detect and remove precancerous lesions such as multifocal high-grade pancreatic intraepithelial neoplasia (PanIN) lesions and IPMN with high-grade dysplasia (Shi et al 2009, Matthaei et al 2011, Lucas et al 2013 in patients eligible for pancreatic surgery (Klapman & Malafa 2008, Bartsch et al 2016.…”

“…The loss of functional BRCA2 gene in tumor tissue impairs HR function. For example, Lucas et al (2013) reported a loss of heterozygosity in 50% of BRCA1-associated and 75% of BRCA2-associated PDAC in a series of 39 BRCA1/2 mutation carriers with Jewish Ashkenazi ancestry. In addition, micro-dissection of PDAC samples from IPMN in one patient revealed partial and complete loss of heterozygosity in IPMN and PDAC lesions, respectively.…”