BACKGROUND-Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer.

Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (Kras G12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of Kras G12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, Kras Pancreatic ductal adenocarcinoma has a median survival of 6 months and a 5-year survival of <5%, making it one of the most lethal human cancers (Warshaw and Fernandez-del Castillo 1992). This poor prognosis relates to the uniformly advanced disease stage at the time of diagnosis and to its profound resistance to existing therapies. A number of key challenges must be addressed to permit improvements in patient outcome, including the need to understand more definitively the cellular origins of this disease, to elucidate the biological interactions of the tumor cell and stromal components, to determine the role of specific genetic lesions and their signaling surrogates in the initiation and progression of the tumor, and to uncover the basis for the intense therapeutic resistance of these cancers ).This malignancy is thought to arise from the pancreatic ducts on the basis of its histological and immunohistochemical relationship to this cell type (Solcia et al. 1995). Consistent with a ductal origin, premalignant lesions, known as pancreatic intraepithelial neoplasms (PanINs)-which are thought to arise from the smaller pancreatic ducts-are found in close physical contiguity with advanced malignant tumors (Cubilla and Fitzgerald 1976;Hruban et al. 2001). PanINs appear to progress toward increasingly atypical histological stages and display the accumulation of clonal genetic changes, suggesting that they are precursors of ductal adenocarcinoma

High-frequency microsatellite instability in colorectal cancer is independently predictive of a relatively favorable outcome and, in addition, reduces the likelihood of metastases.