Abstract
Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2. Positive results have been reported with the use of targeted therapies, particularly poly (ADP-ribose) polymerase inhibitors in BRCA-mutated ovarian and breast cancers, and their use is currently being investigated in germline-mutated pancreatic cancer. The aim of this review is to provide an outline of germline DNA damage repair mutations in pancreatic cancer and their effect on the incidence, outcomes and responses to different therapeutic options.
Highlights
Pancreatic cancer is the 10th most common cancer in the UK (2013) and 12th most common cancer in the US [1, 2]
The resection rate of pancreatic ductal adenocarcinoma (PDAC) for cyclin-dependent kinase inhibitor 2A (CDKN2A) mutation carriers was 75%, and the 5-year survival rate 24%. As this resection rate and the survival data at 5 years was better than historical controls at that time, this study demonstrated that surveillance of CDKN2A mutation carriers was relatively successful with different combinations of magnetic www.impactjournals.com/oncotarget resonance imaging (MRI), endoscopic ultrasound (EUS) and magnetic resonance cholangiopancreatography (MRCP) [48] in the context of this trial, detecting most PDACs at a resectable stage
Pancreatic cancer is a deadly disease with short overall survival and the need for new treatment options is crucial
Summary
Pancreatic cancer is the 10th most common cancer in the UK (2013) and 12th most common cancer in the US [1, 2]. In the more recent study, published in 2016, the same group performed WGS and deep-exome sequencing with gene copy number analysis on 456 samples from patients with PDAC and their histopathological variants They reported germline mutations in 5% and somatic mutations in 12% in the BRCA pathway (BRCA1, BRCA2, ATM and PALB2). Roberts et al demonstrated that among familial pancreatic cancer probands, 4/166 (2.4%) carried deleterious ATM mutations and the numbers were even higher (4.6%) in families with more than 3 affected members [54] These studies exhibited that ATM loss plays a role in pancreatic cancer but the clinical significance of this aberration is still unknown, as there are no trials that have targeted this specific mutation in patients with PDAC. Advanced or Recurrent Solid Tumours ongoing, but US, UK not recruiting participants
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