KIT and PDGFRA Wild-type GISTs: ESMO Biomarker Factsheet

Approximately 15% of GISTs do not have detectable mutations in the receptor tyrosine kinase genes, KIT or PDGFRA, and are generally termed ‘wild-type’ (wt) GISTs^[1-3]. These are the primary form of GIST found in children. The wt GISTs harbour other genomic aberrations, including mutations in BRAF, NF1, NTRK and subunits of the succinate dehydrogenase (SDH) complex^{[1, 2, 4-6]}. The wt GISTs are rare, which has made it difficult to determine their clinical and genetic features^{[1, 3]}. Analysis of a large cohort of patients with wt GIST (n=95) identified three molecular subtypes—two types of SDH-deficient GIST (SDH-mutant and SDH-epimutant) and SDH-competent GIST (characterised largely by BRAF, NF1 or more rare gene mutations). This classification identifies two distinct diagnostic groups with implications for prognosis and clinical management: SDH-competent GISTs (sharing tumour and demographic features with KIT/PDGFRA-mutated GISTs) and SDH-deficient GISTs (frequently associated with syndromic GIST and harbouring molecular lesions of SDH subunits)^[3].

SDH-deficient wt GIST

SDH deficiency is the most frequent molecular alteration in wt GIST^{[3, 7, 8]}. SDH is a mitochondrial enzyme complex comprised of four subunits—SDHA, SDHB, SDHC, and SDHD—whose genes map to 5p15.33, 1p36.13, 1q23.3, and 11q23.1, respectively^[4]. Located in the inner mitochondrial membrane, the SDH complex plays a role in the electron transport chain and Krebs cycle, catalysing the oxidation of succinate to fumarate^{[1, 4]}. Deficiency of SDH complex leads to accumulation of succinate, resulting in hypoxia-inducible factor (HIF)1-α stabilisation and constitutive activation of hypoxic signalling and tumorigenesis^{[1, 4]}. In parallel, succinate accumulation also inhibits key enzymes that regulate the epigenome leading to hypermethylation of DNA and histones^{[9, 10]}.

Deficiency of SDH in GIST can arise either from mutation in one of the genes encoding the SDH subunits, SDHA, SDHB, SDHC or SDHD (collectively referred to as SDHx mutations) or through epigenetic silencing of SDHC (inactivation through promoter hypermethylation)^{[3, 7, 10]}. A large proportion of GIST SDHx-mutations are present in the germline, which has implications for genetic counselling and testing of first-degree relatives of these patients^{[3, 11]}.

SDH-deficient GISTs are diagnosed predominantly in female paediatric or young adult patients, and are characterised by unique clinical, morphological and genetic features^{[1, 3, 4, 12]}. These tumours are predominantly gastric in location, with epithelioid histology and multilobulated/multinodular growth pattern and frequently metastasise to lymph nodes, liver or peritoneal cavity, although generally exhibiting an indolent long-term clinical course^{[1, 3, 12, 13]}. Conventional risk stratification parameters appear not to predict metastatic progression of SDH-deficient GISTs as even small, mitotically inactive SDH-deficient GISTs may metastasise, and when metastases do occur they may be strikingly indolent, sometimes remaining stable for years or decades^{[1, 4, 14]}. SDHA mutated-GIST have been associated with a more indolent course of disease compared with KIT/PDGFRA mutated GIST and wt SDH-competent GIST^[13].

SDH-deficient GISTs are characterised by a pattern of global, genome-wide DNA hypermethylation^{[3, 10]}, and frequently overexpress insulin-like growth factor 1 receptor (IGF1R)^{[15, 16]}.

SDH-deficient GISTs can be sporadic, with no other clinical manifestations, but more frequently present as one of two classes of syndromic GISTs, Carney triad and Carney- Stratakis syndrome^{[11, 17, 18]}. Carney-Stratakis syndrome, an inherited predisposition syndrome to multiple gastric GISTs and paragangliomas, is caused by SDHx germline mutations^{[1, 3, 6, 14]}. Surveillance for paragangliomas and other tumours is indicated for patients with inherited SDH-deficient GISTs^[4]. Carney-triad, a non-heritable syndrome characterised by multiple gastric GISTs, paragangliomas and pulmonary chondromas, is generally associated with epigenetic SDH inactivation through SDHC hypermethylation^{[10, 19]}, and has been rarely associated with germline SDH mutations^[20].

SDH-competent GIST

SDH-competent wt GISTs are primarily comprised of tumours harbouring mutations in components of cell signalling pathways, including BRAF and NF1, that act downstream of the receptor tyrosine kinases^[1]. SDH-competent GISTs generally share tumour and patient characteristics with those of KIT/PDGFRA-mutated tumours: they exhibit normal genomic methylation patterns, are generally sporadic, presenting predominantly in older adults, located in either the stomach or small bowel, with spindle cell histology. They rarely metastasise to lymph nodes but generally follow a more aggressive course of disease compared to SDH-deficient tumours^[3].

Mutations in the tumour suppressor gene, NF1, cause syndromic neurofibromatosis type I (NF1), and have also been identified in patients with KIT/PDGFRA wt GIST^{[1, 4, 5]}. The NF1 gene encodes neurofibromin, which negatively regulates the RAS–RAF–MEK–ERK signalling pathway downstream of receptor tyrosine kinases such as KIT and PDGFRA^{[4, 5]}. Patients with NF1 appear to be overrepresented among GIST patients and GISTs occur in approximately 5–25% of NF1 patients^{[1, 21]}. NF1- associated GISTs are characterised by duodenum and small intestine location, small size, tumour multiplicity, and low mitotic rates^{[1, 5]}. These tumours generally follow an indolent clinical course reflected in low recurrence and metastases rates, although NF1-associated GISTs arising from the duodenum can display an aggressive behaviour, being large mitotically active tumours with pronounced metastatic potential^{[1, 5, 21]}.

BRAF is a key intracellular protein kinase also involved in the RAS–RAF–MEK–ERK signalling pathway and is mutated in a wide range of cancers, including malignant melanoma, thyroid cancer and colorectal cancer^{[22, 23]}. Multiple studies have identified BRAF mutations in KIT/PDGFRA wt GISTs, with a prevalence of up to 13%^{[22, 24-27]}. Like other tumour types in which BRAF mutations are common, BRAF mutations in GIST predominantly involve the exon 15 V600E hot spot^{[1, 22, 24-27]}. BRAF-mutated GISTs appear to predominantly arise in the small intestine and generally share clinicopathological features characteristic of KIT/PDGFRA-mutated GISTs^{[22, 25]}.

Other genomic aberrations affecting oncogenes and tumour suppressors have been identified in SDH-competent wt GISTs including mutations in PIK3CA, NRAS, HRAS, KRAS, and gene fusions including ETV6-NTRK3 and FGFR1-TACC1; however, the numbers of patients with these different mutations remains small, such that genotype-phenotype correlations are not yet possible^[4].

Treatment response in KIT/PDGFRA wt GIST

The scarcity of KIT/PDGFRA wt GISTs makes it difficult to identify any relationship between their genotype and response to conventional systemic tyrosine kinase inhibitor therapies, such as imatinib, sunitinib, and regorafenib, used for non-wt GIST^{[1, 3]}.

Multiple studies have previously demonstrated that KIT/PDGFRA wt GISTs are characterised overall by poor responses to standard imatinib therapy in both the advanced and adjuvant GIST treatment setting, with a 76% greater risk of death reported for patients with advanced wt GIST compared with those with KIT exon 11 mutations^{[4, 28-30]}. IGF1R amplification, observed primarily in SDH-deficient GIST, and signalling pathway mutations downstream of KIT and PDGFRA (like NF1 and BRAF exon 15 V600E mutations) in SDH-competent GIST, may represent alternative mechanisms of imatinib resistance in KIT/PDGFRA wt tumours^{[1, 16, 25, 31, 32]}.

SDH-deficient GIST have generally demonstrated poor responses to imatinib. For instance, only one of 49 patients treated with imatinib had a partial response^[3]. By contrast, antiangiogenic agents may have some activity: seven of 38 patients with SDH-deficient GISTs showed responses to sunitinib^[3] and six patients experienced clinical benefit from regorafenib^[33]. A current clinical trial at NCI is investigating guadecitabine in epigenetic SDH-deficient GIST (NCT03165721).

While SDH-competent GISTs are generally considered to be less responsive to the conventional tyrosine kinase inhibitors, identifying tumour mutations might prove useful in determining appropriate treatment^{[1, 3]}. For example, emerging data suggest that BRAF-mutated GIST may respond to BRAF inhibitors such as dabrafenib^[34], and MEK inhibitors, such as selumetinib, may have utility in NF1-mutated GIST^[3]. Responses to a neurotrophic tropomyosin receptor kinase (NTRK) inhibitor in patients bearing GIST with NTRK fusion have also been reported^[35].

Molecular testing of KIT/PDGFRA wt GIST

All GIST with no detectable KIT or PDGFRA mutations should be analysed by SDHB immunostaining. If a GIST is SDH-deficient by SDHB-IHC, sequencing of SDHx in the tumour and germline should be performed^[3]. If no SDH mutation is identified, then the presence or absence of SDHC promoter methylation should be determined^[3]. If an SDHx mutation is found in the germline then genetic counselling is indicated, together with mutation screening of first-degree relatives, and regular screening for paraganglioma, pheochromocytoma, or other tumours^{[3, 4]}. SDHC promoter hypermethylation is generally not germline, therefore genetic counselling for these patients is not required, but do still require screening for paragangliomas, as they are often associated with syndromic GIST^[3].

SDHB-competent cases should be analysed by next-generation sequencing assays to identify potential other targetable alterations (BRAF, NF1, NTRK, FGFR1…).

References

Last update: 05 Jul 2018

Table of Contents

SDH-deficient wt GIST

SDH-competent GIST

Treatment response in KIT/PDGFRA wt GIST

Molecular testing of KIT/PDGFRA wt GIST

References

Author

Antoine Italiano

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