Consensus points in clinical management of GIST as well as questions for future clinical trials were identified during this consensus conference on GIST management.
Entry of quiescent cells into the cell cycle is driven by the cyclin D-dependent kinases Cdk4 and Cdk6. These kinases are negatively regulated by the INK4 cell cycle inhibitors. We report the generation of mice defective in P15 INK4b and P18 INK4c . Ablation of these genes, either alone or in combination, does not abrogate cell contact inhibition or senescence of mouse embryo ®broblasts in culture. However, loss of P15 INK4b , but not of P18 INK4c , confers proliferative advantage to these cells and makes them more sensitive to transformation by H-ras oncogenes. In vivo, ablation of P15 INK4b and P18 INK4c genes results in lymphoproliferative disorders and tumor formation. Mice lacking P18 INK4c have deregulated epithelial cell growth leading to the formation of cysts, mostly in the cortical region of the kidneys and the mammary epithelium. Loss of both P15 INK4b and P18 INK4c does not result in signi®cantly distinct phenotypic manifestations except for the appearance of cysts in additional tissues. These results indicate that P15 INK4b and P18 IKN4c are tumor suppressor proteins that act in different cellular lineages and/or pathways with limited compensatory roles.
Deletions affecting codons 557 to 558 are relevant for the prognosis of RFS in GIST patients. This critical genetic alteration should be considered to be a new prognostic stratification variable for randomized trials exploring imatinib mesylate in the adjuvant setting in GIST patients.
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