**Background:** Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract originating from interstitial cells of Cajal. Approximately 10–15% of adult GISTs and all pediatric GISTs lack driver mutations in KIT and PDGFRA, and are classified as wild-type (WT) GISTs. Among WT GISTs, 20–40% are driven by loss of function of the succinate dehydrogenase (SDH) complex, termed SDH-deficient GISTs. SDH deficiency is caused by biallelic inactivation of one of four SDH subunit genes (SDHA, SDHB, SDHC, SDHD) or, in about half of cases, by hypermethylation of the SDHC promoter (epimutation). SDHA mutations are the most common subunit alteration, occurring in ~30% of SDH-deficient GISTs. This review focuses specifically on the prevalence and characteristics of germline SDHA mutations in this population.
**Methods:** The authors conducted a comprehensive literature review of all studies reporting SDHA-mutated GISTs, with particular emphasis on the prevalence of germline mutations in SDH-deficient GIST populations harboring SDHA somatic mutations. Data were collected from multiple studies published between 2011 and 2022, including case series and cohort studies. The review compiled a table of 62 reported germline SDHA mutations with available clinical and molecular details.
**Key Results:** Across the reviewed studies, germline SDHA mutations were found to be highly frequent in SDHA-deficient GISTs. In a 2013 study by Dwight et al., 30% of SDH-deficient GISTs in a series of 10 patients were associated with germline SDHA mutations. Oudijk et al. identified germline mutations in 4 of 33 WT GISTs tested. In a cohort of 11 SDHB-negative WT GISTs, 5 patients (45%) carried SDHA mutations, with 3 confirmed as germline. A large 2016 study of 95 patients (84 SDH-deficient) found that among 63 SDH-mutant GISTs, 34 had SDHA mutations, of which 20 were germline. Most notably, a recent study identified germline mutations in all 14 patients analyzed for whom normal counterpart tissue was available. The most common mutation across all series was c.91C>T (p.R31X) in exon 2 of SDHA, which produces a premature stop codon at position 31. This mutation was reported in at least 20 of the 62 tabulated cases. SDHA-mutant patients typically carry two mutational events at the SDHA locus—either loss of the wild-type allele or a second somatic event in compound heterozygosis. All SDHA-mutant GISTs were localized in the stomach. Patients with SDHA-mutant tumors tend to have an older median age compared to SDH-deficient GISTs due to other subunit mutations. SDHB, SDHC, and SDHD mutations in GIST occur in only 20–30% of cases, and most of these are also germline. In the Boikos et al. study, within 63 SDH-mutant GISTs, 54% had SDHA mutations (mostly germline), while SDHB/C/D together represented 46%. Only a minority of SDHA-mutant tumors (9 of 25 available samples) showed loss of heterozygosity as the second hit, compared to most SDHB-mutant tumors (12 of 13). SDH-deficient GISTs are characterized by immunohistochemical loss of SDHB expression, while SDHA immunohistochemistry specifically identifies SDHA-mutant GISTs. Clinically, SDH-deficient GISTs tend to develop in children and young patients, are primarily gastric, exhibit multi-nodular growth and epithelioid phenotype, and frequently involve lymph node metastases but follow an indolent disease course. They respond poorly to imatinib. Regarding treatment, there is consensus to avoid imatinib or adjuvant therapy in this subset. Anti-angiogenic TKIs (sunitinib, regorafenib, pazopanib) show some activity. The IGF-1R TKI linsitinib showed a clinical benefit rate of 40% and progression-free survival at 9 months of 52% in a phase II study including 15 SDH-deficient GISTs. A phase II trial of temozolomide is ongoing (NCT03556384).
**Clinical Implications:** The high incidence of germline SDHA mutations in SDHA-deficient GISTs has important implications for genetic counseling. Since the majority of SDHA-mutated GISTs carry germline mutations, all patients with SDH-deficient GISTs should be considered for germline testing. The consistent loss of SDHA expression in tumors predicts the presence of SDHA mutations, making immunohistochemistry a reliable screening tool. The c.91C>T (p.R31X) mutation's high frequency across different geographic populations suggests it may be a hotspot mutation rather than a founder effect. Most SDHA mutations in GISTs appear to be GIST-specific, with only rare associations with paraganglioma, pulmonary chondroma, or Carney triad. Currently, there are no specific surveillance guidelines for SDHA germline mutation carriers, and follow-up should parallel that of the general GIST population. The increasing detection of SDHA variants of unknown significance (VUS) through next-generation sequencing presents clinical challenges, as VUS should not be used in clinical decision-making.