V600E<i>BRAF</i>mutations are alternative early molecular events in a subset of<i>KIT/PDGFRA</i>wild-type gastrointestinal stromal tumours

Agaimy, Abbas; Terracciano, Luigi; Dirnhofer, Stefan; Tornillo, Luigi; Foerster, Anja; Hartmann, Arndt; Bihl, Michel

doi:10.1136/jcp.2009.064550

Cited by 196 publications

(143 citation statements)

References 26 publications

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“…Wild-type GISTs include tumors with mutations downstream of KIT; 10,50,131,132 hence, these subsets of wild-type GISTs might respond better to other targeted agents, such as VEGFR inhibitors for pediatric/SDH-deficient GIST and BRAF/MEK inhibitors for BRAF and RAS mutant GIST. 133 …”

Section: Primary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Section: Primary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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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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“…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%