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Defects in the tricarboxylic acid (KREBS) cycle genes in tumorigenesis


For this effort all top European cancer research groups working on the association between defects in the tricarboxylic acid cycle (TCAC) and cancer form a consortium to 1) profoundly characterize the human phenotypes to enable identification and efficient cancer prevention, and 2) to unravel the underlying molecular mechanisms. Recent breakthrough findings by the consortium participants and others have shown that defects in at least four TCAC genes - fumarate hydratase (FH, fumarase), and succinate dehydro genase (SDH) B, C, and D - can confer susceptibility to cancer. We shall take these studies forward by characterizing the natural history of the syndromes in large European materials. Simultaneously, we shall perform functional studies to elucidate the cel lular events induced by these defects by systems biology approaches including functional studies in cell lines, model organisms, and transcription profiling of TCAC deficient and proficient tumors and models. TCAC defect associated expression patterns will be utilized to examine other cancer types for such defects. We have evidence that modifying genes play a key role in TCAC defect associated tumorigenesis, and candidate regions have been identified. Following gene identification, the possible role of thes e modifiers in low penetrance cancer predisposition in the general population will be examined. The rationale to form this consortium is simple and strong. The consortium brings together the key European cancer researchers studying TCAC associated tumorige nesis. Studying separately the tumorigenic effects of FH and the different units of SDH would be ineffective, and formation of the consortium will ensure that Europe will maintain the initiative in this new and exciting field of research. The deliverables arising from the workpackages will contribute to the common goals; prevention of TCAC associated cancers, and learning the lessons these lesions can teach to cancer #

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