Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST

Abstract

on behalf of GIST Study GroupMutations of genes encoding the subunits of the succinate dehydrogenase (SDH) complex were described in KIT/PDGFRA wild-type GIST separately in different reports. In this study, we simultaneously sequenced the genome of all subunits, SDHA, SDHB, SDHC, and SDHD in a larger series of KIT/PDGFRA wild-type GIST in order to evaluate the frequency of the mutations and explore their biological role. SDHA, SDHB, SDHC, and SDHD were sequenced on the available samples obtained from 34 KIT/PDGFRA wild-type GISTs. Of these, in 10 cases, both tumor and peripheral blood (PB) were available, in 19 cases only tumor, and in 5 cases only PB. Overall, 9 of the 34 patients with KIT/PDGFRA wild-type GIST carried mutations in one of the four subunits of the SDH complex (six patients in SDHA, two in SDHB, one in SDHC). WB and immunohistochemistry analysis showed that patients with KIT/PDGFRA wild-type GIST who harbored SDHA mutations exhibited a significant downregulation of both SDHA and SDHB protein expression, with respect to the other GIST lacking SDH mutations and to KIT/PDGFRA-mutated GIST. Clinically, four out of six patients with SDHA mutations presented with metastatic disease at diagnosis with a very slow, indolent course. Patients with KIT/PDGFRA wild-type GIST may harbor germline and/or de novo mutations of SDH complex with prevalence for mutations within SDHA, which is associated with a downregulation of SDHA and SDHB protein expression. The presence of germline mutations may suggest that these patients should be followed up for the risk of development of other cancers.

Gastrointestinal stromal tumors: what do we know now?

“…The absence of immunostaining for SDHA, as well as SDHB, is helpful in identifying GISTs with possible SDH gene mutations. 58,58,[62][63][64][65][66] Approximately 50% of wild-type GISTs demonstrate high expression of IGF1R. 67 In SDH-deficient GISTs, upregulation of IGF1 and IGF2 may activate IGF1R in an autocrine manner (Figure 3b), resulting in signaling through both the MAP kinase and PI3 kinase/AKT pathways.…”

Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations

“…All six patients with SDH-deficient GIST had SDHA-mutant GIST, and all cases except two have been previously described. 2,4,7 None of the five patients with KIT/PDGFRA wild-type non-SDH-deficient GIST had mutations in any SDH complex subunits.…”

Molecular features and genetic markers of gastrointestinal stromal tumors

“…В опухолях с дефицитом SDH активируется транскрипционный фактор HIF, повышающий экс-прессию фактора роста эндотелия сосудов VEGF, что ведет к пролиферации и ангиогенезу в условиях псевдогипоксии [85]. Мутации SDHA и SDHB могут быть герминальными при синдроме Карнея-Страта-киса или спорадическими [85][86][87][88][89]. Наиболее часто в SDHA-дефицитных ГИСО встречаются мутации SDHA, в частности герминальная мутация SDHA (R31Х на уровне белка), в результате которой прерывается синтез белка [89], что вызывает нарушения в комплек-се транспорта электронов.…”

“…Выявлены также новые мутации Q54X, T267M и кодон 1663+3G>C [87]. Уста-новлено, что в опухолях с мутацией SDHA снижена экспрессия как SDHA, так и SDHB [88].…”