Molecular advances in pancreatic cancer.

Our understanding of the molecular genetics of pancreatic cancer has advanced spectacularly over the last 5 years so that this tumour type is now one of the best characterised of all malignancies. A small proportion of cases results from inherited predisposition due to germline transmission of a mutated CDKN2 or BRCA2 gene, while patients with familial pancreatitis due to a mutated cationic trypsinogen gene have a greatly increased risk of developing pancreatic cancer. The majority of cases are sporadic and are characterised at the molecular level by several key genetic abnormalities. The most frequent of these is point mutation of the dominant oncogene KRAS, a lesion which occurs as an early and possibly initiating event in tumourigenesis. Inactivating mutations of the tumour suppressor genes TP53, CDKN2 and SMAD4 are also frequently observed and this constellation of genetic defects sets pancreatic cancer apart from other types of cancer, a feature which could have important implications for molecular diagnosis. Genetic intervention for cancer prevention and therapy is becoming a clinical reality and several approaches are being pursued for pancreatic cancer. As well as tumour suppressor gene replacement and oncogene blockade, strategies with a potential bystander effect are showing promise. These include genetic prodrug activation therapy using selective expression of suicide genes and genetic immunomodulation with cytokines and tumour-associated antigens.