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  • Pancreatic cancer is the fourth leading cause of cancer death in the United States, with an estimated 38,000 American deaths in 2013. Worldwide it causes approximately 227,000 deaths each year and is the eighth most common cause of cancer-related death. The major type, pancreatic ductal adenocarcinoma, is a nearly uniformly metastatic and fatal disease, and the mortality rate for pancreatic ductal adenocarcinoma closely follows that of the incidence. Pancreatic cancer presents clinically with pain, with symptoms related to obstruction of the biliary or pancreatic ducts, or with protean symptoms such as weight loss and cachexia. Pancreatic neuroendocrine tumor is a separate major category of pancreatic neoplasms, often has endocrine clinical sequelae, and is less frequently metastatic and fatal.

  • Although most carcinomas of the pancreas appear to be sporadic, studies suggest that 3-10% of all cases of pancreatic ductal adenocarcinoma are hereditary. Some of the genes responsible for the familial aggregation of pancreatic cancer are known, and they most convincingly include germline mutations in the BRCA2, PALB2, CDKN2A, PRSS1, ATM, STK11/LKB1, and DNA mismatch-repair genes.

  • The profile of somatic genetic mutations in pancreatic cancer is distinct from other neoplasms. The KRAS oncogene is commonly activated by somatic mutations in pancreatic cancer, whereas three tumor-suppressor genes are commonly inactivated. Ninety percent or more of pancreatic cancers harbor activating point mutations in codon 12 of KRAS. The CDKN2A tumor-suppressor gene is inactivated in 90-100% of pancreatic cancers, TP53 in 75%, and SMAD4 in 50%. In addition, recurrent somatic mutations of the MKK4, STK11/LKB1, TGFβ receptors, Smad and Fanconi anemia pathways, ATM, and ARID1A genes have also been reported. Various loci of gene amplifications each affect a minority of carcinomas.

  • Inactivation of the SMAD4 gene may be rather specific for pancreatic ductal adenocarcinoma. SMAD4 is inactivated in as few as 15% of metastatic colorectal cancers and in less than 10% of other major cancer types. SMAD4 belongs to a class of proteins that mediate signals of the TGF-β superfamily.

  • Microsatellite instability (RER+) is seen in a small minority (~ 4%) of pancreatic cancers. These RER+ cancers have a characteristic histologic appearance (medullary histology) and frequently have wild-type KRAS gene.

  • The diagnosis of pancreatic cancer is suspected based on clinical findings, and often can be confirmed with radiologic and endoscopic techniques. Effective screening tests are not available yet. However, DNA-based testing appears promising.

  • Recently, the exomes of the four most common cystic neoplasms of the pancreas have been sequenced, and each cyst type has its own unique mutational profile. Serous cystic neoplasms are characterized by VHL mutations, solid-pseudopapillary neoplasms harbor CTNNB1mutations, intraductal papillary mucinous neoplasms have GNAS, RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 gene mutations, and mucinous cystic neoplasms have RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 alterations.

  • DAXX, ATRX, MEN-1 and mTOR pathway genes are mutated in pancreatic neuroendocrine tumors.


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