Prevalence of Germline Pathogenic Mutations in Patients With Pancreatic Adenocarcinoma

Background Pancreatic ductal adenocarcinoma has poor prognosis mainly highlighted by the low 5-year survival rate, which is estimated to be around 6%. Although pancreatic cancer incidence is approximately 0.5% in the general population, it has a high-mortality rate. It is being registered as the fourth leading cause of cancer-related deaths in the United States. Poor prognosis is mainly attributed to the lack of efficient treatment options.

With the majority of pancreatic adenocarcinoma cases being sporadic, familial clustering (defined by the presence of at least two first degree relatives with pancreatic cancer) is observed in ~20% of the cases, whereas a clear genetic cause is identified in approximately half of these cases. Pancreatic cancer is known to occur in a range of cancer predisposing syndromes, such as hereditary breast and ovarian cancer, Peutz-Jeghers, familial adenomatous polyposis, Lynch, Li-Fraumeni and familial atypical multiple mole syndromes, while there have been clear associations with loss-of-function mutations in non-syndromic cancer genes, such as PALB2 and ATM. In addition, individuals carrying mutations in PRSS1 gene that predisposes for hereditary pancreatitis are also considered to be at high-risk for pancreatic cancer. It is therefore clear that pancreatic cancer is not related with a single cancer predisposition gene, but with numerous known and probably yet to be discovered, cancer susceptibility genes.

On the other hand, the accurate fraction of genetic predisposition in pancreatic cancer hasn't been determined. Previous studies have evaluated the prevalence of loss-of-function mutations in known cancer predisposition genes in pancreatic cancer patients through the use of multi-gene panels. The mutation yield ranged from 3.8% to 9.7% in genes that were previously found relevant to pancreatic cancer predisposition.

Through these studies, it has been highlighted that family history and stage of pancreatic cancer or age at diagnosis is not always a predictor of an underlying genetic factor, while phenotypic heterogeneity is usually associated with mutation status. The search for novel predisposition genes in pancreatic cancer patients without family history is ongoing through candidate genes analysis or through whole exome sequencing.

Research methodology Clinicopathological characteristics