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The best known association between SDH complex II germline mutations and other tumors is represented by the Carney Stratakis syndrome which is characterized by the occurrence of KIT and PDGFRA WT GIST and paraganglioma. This NVP-AUY922 syndrome is associated with germline point mutations or large deletions of the genes encoding the SDHB, SDHC or SDHD subunits. Strikingly, inactivating germline mutations in SDHB or SDHC genes have been also iden tified in sporadic WT GISTs occurring in patients with out a personal or family history of paraganglioma. The SDHA gene encodes the major catalytic subunit of the succinate dehydrogenase complex II. Germline mutations in SDHA are associated with neurodegenera tive diseases such as an early onset encephalopathy, known as Leigh syndrome and a late onset optic atrophy, ataxia and myopathy.
Until recently, no genetic link between SDHA and cancer could be estab lished. However, two recent studies allowed the identifi cation of SDHA germline mutations in at least 3% patients with apparently sporadic cases of paraganglioma or pheochromocytoma. Interestingly, four cases of sporadic KIT and PDGFRA WT GIST occurring in one pediatric and three young adult patients have also been associated with germline mutation of SDHA. In the present study, we investigated a series of 17 appar ently sporadic and Carneys triad related KIT and PDGFRA WT GIST for SDHA mutations and found an additional two cases with mutations in this gene. These were exclusively present in apparently sporadic cases oc curring in young adults. The p.
Arg31X SDHA germline mutation identified in our study leads to a truncated protein. An identical mutation has been previously reported in four Dutch patients with paraganglioma and in one young adult patient with sporadic WT GIST. The second SDHA mutation identified in our study has been reported as a single nucleotide polymorphism. However, none of the other 16 GIST cases tested showed this change and this mutation was found only in the tumor DNA, but not in corresponding normal DNA of the patient. Furthermore, this tumor showed significant loss of SDHA protein expression by both western blot and IHC, suggesting a functional im pact of this genetic alteration. But since only one source of normal DNA was analyzed in this patient, we cannot formally exclude the possibility of germline mosaicism.
Moreover, since we have sequenced only SDHA exons 2, 9 and 13, we cannot exclude also the presence of a germline mutation in one of the other exons. By performing western blotting, we identified a loss of SDHA protein expression in the two mutated cases whereas expression was retained in the non mutated cases. This result was expected in the tumor with the p. Arg31X mutation because this mutation leads to a trun cated SDHA protein. Although the p.