By this method, another young adult WT GIST was identified to harbor a missense mutation in SDHA exon 2. In this latter case, the mutation was observed only in the tumor and not in the normal tissue DNA tested. This patient was alive with disease 15 years after the initial diagnosis, preceding the availability for targeted therapy. One targeted AZD6482 -Adventure No additional muta tions in SDHA exons 9 or 13 were identified. Mutation of SDHA in WT GIST is associated with concomitant loss of both SDHA and SDHB proteins expression To confirm the functional impact of SDHA mutation, we assessed SDHA protein expression by western blotting in seven WT GISTs, including three samples from the two patients with SDHA mutation and four without SDHA mutation. We found that SDHA expression was absent in the two cases har boring a mutation of SDHA and present in the other cases.
In addition, immunohistochemistry for SDHA and SDHB was performed. The WT GIST associated with a germline SDHA mutation showed complete loss of both SDHA and SDHB protein, while the tumor with a somatic, heterozygous SDHA mutation showed significant decreased in SDHA immuno expression, as well as complete loss of SDHB. In contrast, strong and diffuse SDHA reactivity was present in all WT pediatric and young adult GIST tumors tested without detectable SDHA mutations, which matched with a complete loss of SDHB expression. Furthermore, both SDHA and SDHB expression was preserved in a control case of a young adult GIST carrying a KIT exon 11 deletion. Discussion The dysregulation of metabolism in cancer has been established for over 80 years.
Indeed, one of the first identified biochemical hallmarks of cancer cells was a shift in glucose metabolism from oxidative phosphoryl ation to aerobic glycolysis. This metabolic conver sion was considered for a long time a consequence rather than a cause of cancer. However, this vision has been recently challenged by the finding that a significant proportion of familial and apparently sporadic paragan glioma and pheochromocytoma are related to germline somatic mutation of genes encoding proteins of SDH complex II. This complex is a membrane bound enzyme complex linked to the respiratory chain and a member of the Krebs cycle. It consists of 4 subunits the flavoprotein subunit, the iron sulfur protein subunit, and the integral membrane protein subunits. Mutations of one of the gene encoding these subunits impair the activity of this complex and lead to the stabilization and activation of HIF 1a, which in turn activates cell proliferation and angiogenesis. In addition to paragangliomas and pheochromocyto mas, a number of other solid tumors have been asso ciated with mutations in genes encoding the succinate dehydrogenase complex complex II.