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Pancreatic cancer is a highly lethal disease. Most patients with pancreatic cancer remain asymptomatic before the disease reaches an advanced stage. Most pancreatic cancers arise from microscopic non-invasive epithelial proliferations within the pancreatic ducts, called pancreatic intraepithelial neoplasias. As is common in epithelial tumors, carcinogenesis develops through the accumulation of mutations and genetic lesions resulting in activation of oncogenes and inactivation of tumor suppressor genes. Because multiple combinations of mutations can result in the development of pancreatic cancer, disease sub-classes may present different survival strategies requiring multiple targeted intervention strategies. A thorough understanding of the specific cellular and molecular mechanisms of pancreatic cancer development and progression is required to identify early detection strategies, preventative measures, and effective interventions.
The most frequent genetic abnormalities in invasive pancreatic adenocarcinomas are mutational activation of the KRAS oncogene, inactivation of tumor-suppressor genes including CDKN2A, SMAD4, BRCA2, and TP53, gene amplifications, widespread chromosomal losses, and telomere shortening. KRAS mutations and telomere shortening are the earliest known genetic abnormalities recorded, even in low-grade pancreatic intraepithelial neoplasias, and telomere shortening is considered to contribute to chromosomal instability, whereas inactivation of TP53, BRCA2 and SMAD4 happens in advanced pancreatic intraepithelial neoplasias and invasive carcinomas. Genes mutated in a few pancreatic cancers include oncogenes such as AKT2, BRAF, MYB, and EGFR, and tumor-suppressor genes such as STK11, MAP2K4, ACVR1B, ACVR2A, TGFBR1, TGFBR2, FBXW7, and EP300. Structural analysis of mutated genes implicates DGKA, STK33, PIK3CG, TTK, and PRKCG as low-frequency driver mutations. Intraductal papillary mucinous neoplasms harbor many of the genetic alterations recorded in pancreatic intraepithelial neoplasias but with notable differences, for example, intraductal papillary mucinous neoplasms rarely inactivate SMAD4. Genetically engineered mouse models targeting some of the genes most commonly altered in human pancreatic cancer have been developed, and several of these have been used to study mechanisms and investigate therapeutic agents.
Apart from the driver genes discussed above, epigenetic changes can also alter gene function in pancreatic cancers. Epigenetic dysregulation includes alterations in DNA methylation, non-coding RNAs, and histone modifications. Promoter methylation and gene silencing in pancreatic cancers were first reported for the tumor-suppressor gene CDKN2A, of which epigenetic silencing is restricted to neoplasms without genetic inactivation of CDKN2A. Only a few classic tumor-suppressor and DNA-repair genes undergo epigenetic silencing in pancreatic cancers—eg, MLH1 and CDH1 are methylated in a small proportion of tumors. Many other genes are frequent targets of aberrant methylation and gene silencing in pancreatic cancers, including CDKN1C, RELN, SPARC, TFPI2, and others. Some of the most commonly aberrantly hypermethylated genes in pancreatic neoplasms have been evaluated for their diagnostic or biological relevance. Promoter hypomethylation of overexpressed genes has also been reported for several genes, such as SFN, MSLN, and S100A4, and mucin genes.
There are several directions for future studies on pancreatic cancer. First, the correlation of genetic alterations with clinically important features, such as the pattern of recurrence and response to chemotherapy, will facilitate the translation of these findings into clinically useful assays. The Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial has shown that a subset of patients with aberrations in their tumor genomes can be targeted with specific therapies. Better understanding of the mutational landscape will further expand the use of targeted chemotherapy and other therapeutic options. Then, investigation of other types of alterations, including transcriptional, epigenetic, and proteomic alterations, might identify additional targets for novel approaches to diagnosis and therapy. Finally, therapies targeting specific altered genes or pathways will bring personalized medicine to each individual. In patients with BRCA1 or BRCA2 mutations, molecularly targeted therapies inhibiting the enzyme poly (ADP-ribose) polymerase (PARP) may be more effective, and a worldwide clinical trial of olaparib, a small-molecule PARP inhibitor, is in progress.
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