2006 - UZ Leuven

combination of different techniques: mutation analysis (KIT, PDGFRAand NF1), western blotting, array CGH and ex vivo imatinib responseexperiments. We demonstrate that (i) the NF1-related GISTs do nothave KIT or PDGFRA mutations, (ii) the molecular event underlyingGIST development in this patient group is a somatic inactivation of thewild-type NF1 allele in the tumor and (iii) inactivation of neurofibrominis an alternate mechanism to (hyper) activate the MAP-kinasepathway, while the JAK-STAT3 and PI3K-AKT pathways are lessactivated in NF1-related GIST compared with sporadic GISTs. Inconclusion, we report for the first time the molecular pathogenesis ofGISTs in NF1 individuals and demonstrate that this type of tumorclearly belongs to the spectrum of clinical symptoms in NF1.WINNEPENNINCKX V., LAZAR V., MICHIELS S., DESSEN P., STAS M.,ALONSO S.R., AVRIL M.F., ORTIZ ROMERO P.L., ROBERT T.,BALACESCU O., EGGERMONT A.M.M., LENOIR G., SARASIN A., TURSZT., VAN DEN OORD J.J., SPATZ A.: Gene expression profiling ofprimary cutaneous melanoma and clinical outcome. J. Natl. Cancer Inst.,2006; 98(7): 472-482.Background: Gene expression profiling data for human primarycutaneous melanomas are scarce because of the lack of retrospectivecollections of frozen tumors. To identify differentially expressed genesthat may be involved in melanoma progression and prognosis, weinvestigated the relationship between gene expression profiles andclinical outcome in a cohort of patients with primary melanoma.Methods: Labeled complementary RNA (cRNA) from each tissuesample was hybridized to a pangenomic 44K 60-mer oligonucleotidemicroarray. Class comparison and class prediction analyses wereperformed to identify genes whose expression in primary melanomaswas associated with 4-year distant metastasis-free survival among 58patients with at least 4 years of follow-up, distant metastasis, or death.Results were validated immunohistochemically at the protein level in176 independent primary melanomas from patients with a medianclinical follow-up of 8.5 years. Survival was analyzed with a Coxmultivariable model and stratified log-rank test. All statistical testswere two-sided.Results: We identified 254 genes that were associated with distantmetastasis-free survival of patients with primary melanoma. These254 genes include genes involved in activating DNA replicationorigins, such as minichromosome maintenance genes and geminin.Twenty-three of these genes were studied at the protein level;expression of five (MCM4, P = .002; MCM3, P = .030; MCM6, P =.004; KPNA2, P = .021; and geminin, P = .004) was statisticallysignificantly associated with overall survival in the validation set. In a47