EXPRESSION GENETICS IN CANCER - SHIFTING THE FOCUS FROM DNA TO RNA

Expression genetics is a conceptually different approach to the identi fication of cancer-related genes than the search for mutations at the genome level. While mutations lie at the heart of cancer, at least in its early stages, what is recognized here are phenotypic changes usual ly many steps removed from the initiating mutation. Classically cancer geneticists have concentrated on genomic changes and have ignored the productive potential of examining downstream events based on screenin g for differential gene expression between tumor cells and well matche d normal counterparts. Genes involved in cancer affect the normal func tions of many cellular processes: not only proliferation but cell-cell and cell-matrix interactions, DNA repair, invasion and motility, angi ogenesis, senescence, apoptosis, and others. Yet very few cancer-relat ed genes affecting these processes have been identified in human cance rs by classical methods to find mutated genes despite enormous efforts . I report here our success in readily. isolating more than 100 candid ate tumor suppressor genes from human tissue, estimated to represent r oughly 20% of the total genes recoverable by this approach. Half of th e genes are unknown and the other half include representatives of most known cancer processes. Because their expression is lost during cance r progression, they may be useful tumor markers for diagnosis and prog nosis. Because these genes are not mutated, they provide opportunities for pharmacological intervention by inducing their reexpression.