What is the role of genetics in the etiology of pancreatic cancer?

Updated: Oct 02, 2020
  • Author: Tomislav Dragovich, MD, PhD; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Approximately 5-10% of patients with pancreatic carcinoma have some genetic predisposition to developing the disease. [25]

The molecular genetics of pancreatic adenocarcinoma have been well studied. [26, 27, 28] Of these tumors, 80-95% have mutations in the KRAS2 gene; 85-98% have mutations, deletions, or hypermethylation in the CDKN2 gene; 50% have mutations in p53; and about 55% have homozygous deletions or mutations in Smad4. Some of these mutations can also be found in high-risk precursors of pancreatic cancer. For example, in chronic pancreatitis, 30% of patients have detectable mutations in p16 and 10% have K-ras mutations.

Families with BRCA-2 mutations, which are associated with a high risk of breast cancer, also have an excess of pancreatic cancer. [29]

Assaying pancreatic juice for the genetic mutations associated with pancreatic adenocarcinoma is invasive, but it may be useful for the early diagnosis of the disease. [30] However, this approach is problematic, because genetic mutations in the pancreatic juice may be found in patients with inflammatory pancreatic disease.

Certain precursor lesions have been associated with pancreatic tumors arising from the ductal epithelium of the pancreas. The main morphologic form associated with ductal adenocarcinoma of the pancreas is pancreatic intraepithelial neoplasia (PIN). These lesions arise from specific genetic mutations and cellular alterations that contribute to the development of invasive ductal adenocarcinoma. [31]

The initial alterations appear to be related to KRAS2 gene mutations and telomere shortening. Thereafter, p16/CDKN2A is inactivated. Finally, the inactivation of TP53 and MAD4/DPC4 occur. These mutations have been correlated with increasing development of dysplasia and thus with the development of ductal carcinoma of the exocrine pancreas.

Based on more recent data from sequencing of human tumors, pancreatic cancer is a genetically complex and heterogeneous disease. [32] This is confounded by considerable variability in terms of the genetic malformations and pathways involved between individual tumors. In addition, the long time from early to clinically manifested disease (21.2 y on average) allows for an accumulation of complex genetic changes, which probably explains the fact that it is often resistant to chemotherapy and radiation therapy. [33, 34]

The inherited disorders that increase the risk of pancreatic cancer include hereditary pancreatitismultiple endocrine neoplasia (MEN), hereditary nonpolyposis rectal cancer (HNPCC), familial adenomatous polyposis (FAP) and Gardner syndromefamilial atypical multiple mole melanoma (FAMMM) syndrome, von Hippel-Lindau syndrome (VHL), and germline mutations in the BRCA1 and BRCA2 genes.

Hereditary pancreatitis has been associated with a 40% cumulative risk of developing pancreatic cancer at 40%. [23] MEN-1 and VHL are other genetic syndromes associated with pancreatic endocrine tumor development.

Patients with MEN-1 develop symptomatic pancreatic endocrine tumors about 50% of the time, and these pancreatic tumors are noted to be the leading cause of disease-specific mortality. [35] Von Hippel-Lindau syndrome has been associated with malignancy in 17% of masses found in the pancreas in people with this syndrome. [36]

Syndromes associated with an increased risk of the development of colon cancer, such as HNPCC and FAP (and Gardner syndrome), have also shown an increased correlation with existence of pancreatic cancer, but the statistics have not been impressive.

In a cohort study of 1391 patients with FAP, only 4 developed pancreatic adenocarcinoma. No statistics are available to show the incidence of pancreatic cancer in patients with HNPCC. [37]

FAMMM has been shown to increase relative risk of developing pancreatic cancer by 13- to 22-fold and the incidence in sporadic cases to be 98%. [38]

The above disorders have specific genetic abnormalities associated with the noted increased risk of pancreatic cancer. Pancreatic cancer in hereditary pancreatitis is associated with a mutation in the PRSS1 gene. Pancreatic cancer appearing in FAP and HNPCC has been associated with a mutation in the APC gene and MSH2 and MLH1 genes respectively. FAMMM and pancreatic cancer has been associated with a mutation in CDKN2A. Endocrine tumors of the pancreas associated with VHL are thought to develop by way of the inactivation of the VHL tumor suppressor gene. [25]

Germline mutations in BRCA1 and BRCA2 have been shown to moderately increase the risk of developing pancreatic cancer by 2.3- to 3.6-fold, but BRCA2 has been associated more commonly with pancreatic cancer, at an incidence of 7%. [25]

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