Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are usually driven by mutations in KIT or PDGFRA, although 15% of GISTs in adults and 490% in children lack such mutations. The majority of gastric KIT/PDGFRA wild-type GISTs show distinctive morphological and clinical features and loss of expression of succinate dehydrogenase (SDH) B. Only a small subset of SDHB-deficient GISTs carries loss-of-function mutations in SDHB, SDHC, or SDHD. Because of the complexity of its locus (15 exons) and the presence of three pseudogenes, SDHA is rarely analyzed. Recently, mutations in SDHA were shown to lead to loss of expression of SDHA in a small group of paragangliomas. We sought to determine whether immunohistochemistry for SDHA could identify GISTs with SDHA mutations. Tumors (n ¼ 33) with pathological features of SDH-deficient GIST were analyzed for expression of SDHA and SDHB by immunohistochemistry, and SDHA exons were sequenced from tumors lacking SDHA expression. Exons harboring somatic mutations were examined in DNA from corresponding normal tissue. All 33 tumors showed loss of SDHB expression. A total of 9 out of 33 (27%) tumors also lacked expression of SDHA. SDHA-deficient GISTs affected five men and four women (median age 38 years). SDHA expression was intact in the 24 remaining tumors, including those with known SDHB (n ¼ 3) or SDHC (n ¼ 2) mutations. Nonsense (n ¼ 8) or missense (n ¼ 1) mutations in SDHA were identified in all SDHA-deficient tumors. Heterozygous mutations were also found in DNA from normal tissues from six patients with available material. Somatic loss of the second allele has been found in seven tumors, five by loss of heterozygosity, one by a 13-bp deletion, and one by a missense mutation. Loss of SDHA expression in GIST reliably predicts the presence of SDHA mutations, which represent a relatively common cause of SDH-deficient GIST in adults. Immunohistochemistry for SDHA can be used to select patients for SDHA-specific genetic testing.

SDHA mutations in adult and pediatric wild-type gastrointestinal stromal tumors

“…In addition, in an Italian patient the same p.Arg31X was described recently 9 Also, Nannini et al, and Wagner et al, identified the SDHA p.Arg31X mutation (among others) in wild-type and SDHdeficient GISTs, respectively. 25,26 The frequency of SDHA mutations within the SDH-deficient GISTs (36%) of Wagner et al, is slightly higher, but in accordance with our frequency of SDHA-mutated GISTs that show a negative staining of SDHB (25%).…”

Succinate dehydrogenase-deficient renal cell carcinoma: detailed characterization of 11 tumors defining a unique subtype of renal cell carcinoma

“…Recent studies of SDH-deficient paragangliomas and GISTs have demonstrated that only tumors with SDHA mutations show negative SDHA immunohistochemistry (in addition to SDHB). [32][33][34] As expected, there was no abnormality of the SDHB gene detected by next-generation sequencing in this case. Unfortunately, SDHA was not included in the targeted sequencing panel, and therefore, the presence of an inactivating SDHA mutation could not be confirmed.…”

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.…”