Genetic progression of pancreatic cancer.
The progression from normal cells to invasive pancreatic ductal adenocarcinoma (PDAC) requires the accumulation of multiple inherited or acquired mutations. Activating point mutations in the KRAS oncogene are prevalent in pancreatic cancer and result in the stimulation of several pathways including the RAF-mitogen-activated protein kinase pathway and the phosphoinositide 3-kinase pathway. Other genetic alterations, including telomere shortening and the inactivation of tumor suppressor genes such as CDKN2A, TP53, and SMAD4, which encode p16, p53, and SMAD4, respectively, also contribute to the progression of pancreatic cancer. These, and other genetic events, can present at different stages in the development of PDAC at histologically defined precursor lesions known as pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms, or mucinous cystic neoplasms. Each precursor lesion represents alternate routes to PDAC formation and has a unique presentation and somewhat distinct genetic events controlling its development. Despite the advances in the understanding of the genetics of PDAC, the prognosis for this cancer remains poor, and several important aspects of its pathogenesis must be clarified to improve therapeutics, including the timing and method of metastases, as well as the relationship of the tumor cells with the desmoplastic stroma, which is a characteristic feature of the cancer. This review discusses the principal genetic alterations in PDAC and its precursor lesions, including their effects on promoting carcinogenesis.
From the Department of Pathology and Translational Molecular Pathology, Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX.
Robert W
RW
Cowan
Anirban
A
Maitra
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology