Pollard, PJ; (2006) Genetic and functional analysis of tumourigenesis in hereditary leiomyomatosis and renal cell cancer and hereditary paragangliomatosis syndromes. Doctoral thesis , UCL (University College London).

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Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary paragangliomatosis (HPGL) are familial cancer syndromes, caused by germline mutations in genes encoding the Tricarboxylic Acid Cycle (TCAC) enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) respectively. Both FH and SDH function as tumour-suppressor genes and the conditions are inherited as autosomal dominant traits. Germline FH mutations predispose individuals to develop benign smooth muscle tumours of the skin and uterus (leiomyomas) and renal carcinoma, whilst individuals with mutations in SDHB, -C, and -D develop paragangliomas and phaeochromocytomas. In order to study the genetic and functional consequences of FH and SDH mutations, and to elucidate mechanisms of tumourigenesis, which are poorly understood, I have undertaken a comprehensive analysis of tumours from both HPGL and HLRCC patients, using gene and protein expression analysis, metabolomic profiling and cytogenetic analysis of HPGL tumours. Tumours from both syndromes over- express hypoxia-inducible factor-alpha (HIFla), the central signalling protein in hypoxia, and HIFIa-target genes including vascular endothelial growth factor (VEGF) and Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3). HLRCC and HPGL tumours accumulate the TCAC intermediates succinate and fumarate which have been shown to up-regulate HIFla in vitro by inhibiting the prolyl hydroxylases (PHD) that target HIFlct for proteosomal degradation. Therefore, 'pseudo-hypoxia' - the constitutive expression of HIFla in normoxic conditions - is likely to contribute largely to the tumourigenesis of HLRCC and HPGL and is most likely to occur as a direct result of accumulation of TCAC intermediates and PHD inhibition. To further investigate the tumourigenesis of HLRCC, I have successfully created a conditional Fhl (the mouse homologue of human FH) mouse knockout which causes hypertrophy when targeted to smooth muscle. I aim to create further temporal and tissue specific knockouts of Fhl, and if these mice develop tumours provide a model of HLRCC for the testing of anti-cancer drugs and therapies.

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