Gastrointestinal stromal tumors

Liegl‐Atzwanger, Bernadette; Fletcher, Jonathan A.; Fletcher, Christopher D.�M.

doi:10.1007/s00428-010-0891-y

Cited by 240 publications

(173 citation statements)

References 156 publications

(224 reference statements)

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“…3,4 Approximately 15% of GISTs in adults, and 490% of GISTs in children, do not contain identifiable mutations in KIT or PDGFRA and were previously lumped into one group referred to as 'wild-type GIST'. [5][6][7] More recently, these tumors have been subcategorized into genetically defined subgroups, including tumors with activating mutations in BRAF, [8][9][10] loss-offunction mutations in NF1, or loss-of-function mutations in components of the inner mitochondrial membrane Krebs cycle enzyme complex succinate dehydrogenase (SDH). 11,12 This latter group of tumors has been designated 'SDH-deficient GIST'.…”

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confidence: 99%

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

et al. 2013

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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.

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confidence: 99%

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

et al. 2013

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“…[1][2][3][4] GISTs are derived from the interstitial cells of Cajal and up to 95% of these tumors express CD117 (KIT). 1,[4][5][6] Approximately one-third to half of KIT-negative GISTs stain for DOG-1.…”

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confidence: 99%

“…1,[4][5][6] Approximately one-third to half of KIT-negative GISTs stain for DOG-1. 3,7,8 The majority of GISTs arise in the stomach (50-60%) and in the small intestine (30%), other tumor sites include the esophagus, large bowel and rectum (10%). 1,2,4 Most GISTs (75-80%) harbor oncogenic mutations in KIT (receptor for stem cell factor) and an additional 7% in platelet-derived growth factor receptor-a (PDGFRA).…”

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

et al. 2013

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Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-a. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C4T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.

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“…3,4 In contrast, approximately 15% of GISTs in adults and 490% of GISTs in children are categorized as 'wild-type' GISTs because they lack KIT and PDGFRA mutations. [5][6][7] In recent years, a defined set of genetic changes in these so-called wild-type GISTs have begun to be characterized, including activating mutations in BRAF, [8][9][10] loss of function mutations in NF1, 11 and mutations leading to loss of function of the succinate dehydrogenase (SDH) enzyme complex. 12 The SDH enzyme complex is localized to the inner mitochondrial membrane, where it functions both as complex II of the electron transport chain and as a member of the Krebs cycle, converting succinate to fumarate.…”

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confidence: 99%