New Developments in the Molecular Mechanisms of Pancreatic Tumorigenesis

Abstract

Pancreatic cancer is an aggressive disease with a dismal prognosis in dire need of novel diagnostic and therapeutic approaches. The past decade has witnessed an explosion of data on the genetic alterations that occur in pancreatic cancer, as comprehensive next-generation sequencing analyses have been performed on samples from large cohorts of patients. These studies have defined the genomic landscape of this disease and identified novel candidates whose mutations contribute to pancreatic tumorigenesis. They have also clarified the genetic alterations that underlie multistep tumorigenesis in precursor lesions and provided insights into clonal evolution in pancreatic neoplasia. In addition to these important insights into pancreatic cancer biology, these large scale genomic studies have also provided a foundation for the development of novel early detection strategies and targeted therapies. In this review, we discuss the results of these comprehensive sequencing studies of pancreatic neoplasms, with a particular focus on how their results will impact the clinical care of patients with pancreatic cancer.

Figure 1.. Genetic alterations that drive pancreatic tumorigenesis.

Pancreatic ductal adenocarcinoma arises from two different types of precursor lesions: pancreatic intrapeithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Both pathways are defined by common low-risk precursors (LG-PanIN and LG-IPMN), which can give rise to more advanced precursors (HG-PanIN and HG-IPMN) at high risk for transformation to invasive cancer. In both pathways, activating mutations in oncogenes are early events, with KRAS mutation occurring in LG-PanIN and both KRAS and GNAS mutations occurring in LG-IPMN. Tumor suppressor gene loss (including CDKN2A, TP53, and SMAD4 in both pathways as well as RNF43 specifically in IPMNs) occurs in more advanced precursor lesions, often limited to HG-PanIN/HG-IPMN or associated invasive cancer. The timing of mutations in genes altered at low prevalence (“candidate genes”) in these pathways is less clear due to the infrequent occurrence of these mutations.