BRCA1 and BRCA2 Mutation in Pancreatic Cancer: Significance in Therapeutic Approach

Mini Review

Austin J Gastroenterol. 2017; 4(1): 1076.

BRCA1 and BRCA2 Mutation in Pancreatic Cancer: Significance in Therapeutic Approach

Biswas AS¹ and Chakraborty A²*

¹Maulana Abul Kalam Azad University of Technology, India

²Division of Cellular & Molecular Biology, The Hormel Institute, USA

*Corresponding author: Chakraborty A, Cellular & Molecular Biology Division, The Hormel Institute- University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA

Received: January 01, 2017; Accepted: February 27, 2017; Published: March 01, 2017


Germline mutations in the tumour suppressor genes breast cancer antigen gene BRCA1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest challenges in oncology. Though it is estimated that about 5 percent of patients with pancreatic cancer are BRCA carriers, this subset of individuals may be more responsive to therapies that damage DNA, such as some chemotherapies, radiation therapy and some targeted therapies. As a result, BRCA carriers with pancreatic cancer may live longer than their counterparts who do not carry the mutation. We study the therapeutic approach and importance of BRCA1/2 mutation in pancreatic cancer.

Keywords: BRCA1; BRCA2; Pancreatic cancer; PARP; Olyperab


Mutations in BRCA1 and BRCA2, most commonly linked with breast and ovarian cancers. But nowadays it was established that this genes are also associated with pancreatic cancer as well. A person with BRCA1 or BRCA2 mutations has a 5 percent risk to develop pancreatic ductal adenocarcinoma (PDAC) in their lifetime. Mutations in germ line level involving many genes that can lead to develop pancreatic cancer. Such genes are BRCA1, BRCA2 [1,2], TP53 [3], PALB2 [4], P16/CDKN2A [5,6], SMAD4 [7], STK11 [8], ataxia-telangiectasia-mutated (ATM) gene [9] and the mismatch repair genes (MMR) [10]. 5-10% are familial cancer [11-13]. BRCA1 and 2 are autosomal dominant genes having incomplete penitrance [14]. The tumor suppressor genes are those genes which controls cell growth and differentiation and drives tumorigenesis in a cascade pathway manner [15]. BRCA protein involves in post transcriptional protein expression as well a DNA double strand breakage repair by base excision repair method [16].

It was reported that gene expression profiles and somatic genetic changes of BRCA1 and BRCA2 related pancreatic cancer are different from sporadic cases. The histopathological and immunohistochemical characteristics of BRCA mutated patients shown poor prognosis. Despite these findings, conflicting data exist as to whether the prognosis of hereditary pancreatic cancer differs from that of sporadic cases. Some of the discrepancies may be explained by methodological differences or biases. However, no mutation-based studies have shown a survival advantage for BRCA1/2 mutation carriers and several unrelated studies have recently found that the presence of a BRCA1/2 mutation was an independent poor prognostic factor. Germ line mutations in the tumour suppressor genes breast cancer antigen gene BRCA1 and BRCA2 have been proven to portend a drastically increased lifetime risk of breast and ovarian cancers in the individuals who carry them. A number of studies have shown that the third most common cancer associated with these mutations is pancreatic cancer.

Several other lines of evidence also suggest that carriers of BRCA1 or BRCA2 mutations face an increased risk of pancreatic cancer [17,18]. In patients with sporadic pancreatic cancer, BRCA1/2 are mutated in the most advanced pancreatic intraepithelial neoplasia lesions, whereas a germ line mutation in either gene represents the earliest risk factor of patient’s close relatives. It has been reported that pancreatic cancer is the third most common cancer associated with BRCA1/2 mutations [19]. It was found that BRCA2 mutation poses an increased risk for developing pancreatic cancer [20]. Some study proposed BRCA2 as a genetic factor as causes of the pancreatic cancer [21]. As like breast cancer, 5-10% of pancreatic cancer cases are believed to be hereditary. Through analysis of the literature it was found that patients with pancreatic cancer and germ line BRCA2 mutations have a younger than average age of disease onset in case of Ashkenazi Jewish [22]. Satdler, et al. in 2012 established a strong family history of pancreatic cancer in a study among 211 Ashkenazi Jewish Proband. Among them 31% had a first-degree relative with pancreatic cancer, 53% had a second-degree relative and 16% had a third-degree relative diagnosed with the disease [23]. From the study it was established that BRCA1/2 mutations are most important factor to develop familial breast-pancreas cancer families and carriers of the BRCA2 mutation have an increased risk of developing pancreatic cancer. The use of different analysis model can be useful to establish variations in mutation prevalence. This review outlines the therapeutic approach to patients at high risk of developing pancreatic cancer, including criteria for genetic testing.

DNA damage

Different genotoxic agents vary in the type of DNA damage they inflict and the specificity of the induced damage triggers a variety of cellular responses specific to the type of lesion inflicted. While a large host of agents are known to activate checkpoint pathways, two commonly employed agents include IR and ultraviolent (UV) light. IR, by definition, is radiation with sufficient energy to ionize molecules with which it collides [24]. IR can damage DNA directly, or indirectly, through reactive oxygen species intermediates. IR is known to induce a large variety of DNA lesions, the most lethal of which is the DNA Double Stranded Break (DSB). The most lethal form of DNA damage is generally regarded to be the DSB. DSBs are generated endogenously, as a normal part of the cellular process, through replication fork collapse, during DNA replication and in repair events, and by exogenous agents such as ionizing radiation (IR) and other genotoxic compounds. Repair of DSBs is of cardinal importance in preventing chromosomal fragmentation, translocations and deletions. The genomic instability resulting from persistent or incorrectly repaired DSBs can lead to carcinogenesis through activation of oncogenes, inactivation of tumour-suppressor genes, or loss of heterozygosity (LOH) at specific loci, while in the germ line they can lead to inborn defects. The deleterious effects of DSBs have triggered the evolution of multiple pathways for their repair [25].

BRCA1 & BRCA2 function in the DNA damage response

The ability to precisely control the order and timing of cell cycle events is essential for maintaining genomic integrity and preventing mutations able to disrupt normal growth controls. Cells exposed to DNA damaging agents, such as ionizing radiation, coordinately arrest the progression of the cell cycle at the G1/S phase, the S phase and the G2/M phase to allow adequate time for damage repair [26]. It is now widely accepted that both BRCA1 and BRCA2 play multiple critical roles in the maintenance of genome stability as evidenced by a profound number of chromosomal translocations, duplications, and aberrant fusion events between non-homologous chromosomes in BRCA1 and BRCA2 deficient cells. BRCA1 plays a critical role in responding to DSBs through its function in HR. Firstly BRCA1 is recruited to DNA damage sites (Figure 1). Then BRCA1 recruits BRCA2, which facilitates Rad51 filament formation on the ssDNA [27]. Rad51 catalyzes the invasion of the homologous sequence on the sister chromatid, which is then used as template for accurate repair of the broken DNA ends. Other studies have shown that BRCA1 colocalizes with Rad50, a member of the MRN complex, following the induction of DNA damage; Mre11 encodes nuclease activity which resects flush ends of DSBs to generate ssDNA tracts. BRCA1 binds DNA directly and inhibits this Mre11 activity regulating the length and the persistence of ssDNA generation at sites of DNA damage. As ssDNA is a substrate for DNA repair by HR, it appears that BRCA1 might play an essential role in HR-mediated repair of DSBs through its inactivation of Mre11; an idea confirmed by the observation the HR is defective in BRCA1-deficient cells [28]. The roles played by BRCA1 and BRCA2 in the repair of DSBs by HR appear to differ, as evidence indicates a more direct role for BRCA2. The physical interaction between BRCA2 and Rad51 is essential for HR repair of DSBs to take place; BRCA2 is thought to be required for the transport of Rad51 from its site of synthesis to the site of DNA damage, where Rad51 is then released to form the nucleoprotein filament required for HR to take place [28].