Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs?

Nishida, Toshirou

doi:10.21037/tgh.2017.11.05

Cited by 8 publications

(6 citation statements)

References 22 publications

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“…SDH-deficiency represents the most important WT GIST subgroup [17]. These WT GISTs tumors have a higher rate of lymphovascular invasion and liver metastases and they are not expected to respond to tyrosine kinase inhibitor imatinib as they lack KIT or PDGFRα oncogenic mutations [18]. Paradoxically these SDHx deficient GIST tumors seem to be more indolent even in the presence of advanced disease compared to KIT or PDGFRα dependent GISTs [19].…”

Section: Introductionmentioning

confidence: 99%

Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report

Carrera

Beristain

Sancho

et al. 2019

Hered Cancer Clin Pract

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Background Gastrointestinal stromal tumors (GISTs) represent the most frequent mesenchymal tumor of the gastrointestinal tract. Less than 5% of them seem to be hereditary, being succinate dehydrogenase complex ( SDHx ) deficient disorders and neurofibromatosis type 1 the more related inherited conditions. Wild type (WT) KIT and PDGFRα GISTs constitute a clue for a hypothetical underlying germline condition. Case presentation We present a case of a 20 years old female diagnosed of a gastric WT GIST who developed hepatic metastases during her clinical course. No significant or typical phenotypic features suggestive of a specific syndrome were detected by physical examination. Also, her family history seemed to be irrelevant, since no other cases of GISTs, paragangliomas or pheochromocytomas were reported. Her paternal grandfather died as a consequence of a pituitary adenoma. In light of the age of tumor presentation and somatic features of gastric GIST, we performed genetic testing of SDHx genes. Analysis obtained from peripheral blood sample revealed the presence, in heterozygous state, of the c.1A > C; p.(Met1?) pathogenic variant in the SDHA . Conclusions To the best of our knowledge, this is the first published report in which the c.1A > C; p.(Met1?) pathogenic variant in the SDHA is associated with a GIST. SDHA pathogenic variants increase the risk of paraganglioma, pheochromocytoma, GIST, pituitary adenoma and renal cancer in an autosomal dominant inherited condition named paraganglioma syndrome type 5. The absence of family history of tumors in SDHA pathogenic variants carriers could be related to its low penetrance. All patients diagnosed with WT GISTs should be referred to a hereditary cancer genetic counseling unit regardless of the age at presentation or the absence of a suspicious family history.

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Section: Introductionmentioning

confidence: 99%

Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report

Carrera

Beristain

Sancho

et al. 2019

Hered Cancer Clin Pract

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“…For example, GISTs that harbor KIT exon 11 mutations generally respond well to imatinib [24,25], whereas patients with an exon 9 KIT mutation frequently need an increased daily dose of 800 mg/day instead of the regular 400 mg/day to exhibit a treatment response [26]. Furthermore, PDGFRA D842V mutants are resistant to imatinib [27,28], the same as WT-GISTs and GISTs with mutations in genes other than KIT and PDGFRA that display insensitivity to imatinib and other tyrosine kinase inhibitors [29].…”

Section: Current Treatment Of Gastrointestinal Stromal Tumorsmentioning

confidence: 99%

Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors

Amirnasr

Sleijfer

Wiemer

2020

IJMS

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies found in the gastrointestinal tract. At a molecular level, most GISTs are characterized by gain-of-function mutations in V-Kit Hardy–Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog (KIT) and Platelet Derived Growth Factor Receptor Alpha (PDGFRA), leading to constitutive activated signaling through these receptor tyrosine kinases, which drive GIST pathogenesis. In addition to surgery, treatment with the tyrosine kinase inhibitor imatinib forms the mainstay of GIST treatment, particularly in the advanced setting. Nevertheless, the majority of GISTs develop imatinib resistance. Biomarkers that indicate metastasis, drug resistance and disease progression early on could be of great clinical value. Likewise, novel treatment strategies that overcome resistance mechanisms are equally needed. Non-coding RNAs, particularly microRNAs, can be employed as diagnostic, prognostic or predictive biomarkers and have therapeutic potential. Here we review which non-coding RNAs are deregulated in GISTs, whether they can be linked to specific clinicopathological features and discuss how they can be used to improve the clinical management of GISTs.

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“…Tumors lacking c-KIT and PDGFRA mutations should be approached in a step wise fashion starting with testing for SDH status (Figure 2) (31). Immunohistochemical staining with observed loss of the ubiquitously expressed SDHB has proven to be an accurate and cost-efficient diagnostic marker for SDH deficiency (15,17,32,33).…”

Section: Molecular Subtypingmentioning

confidence: 99%

“…In patients with locally advanced disease, metastatic disease or recurrent disease, tyrosine kinase inhibitors, like imatinib mesylate, have offered patients a treatment option with studies demonstrating excellent response (9). However, WT-GISTs in particular remain a challenge as they are generally resistance to imatinib (31).…”

Section: Treatment For Wt-gistmentioning

confidence: 99%

Approach to wild-type gastrointestinal stromal tumors

Kays¹,

Sohn²,

Kim³

et al. 2018

Transl. Gastroenterol. Hepatol

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The discovery of the KIT and platelet derived growth factor receptor alpha (PDGFRA) tyrosine-kinase gain of function mutations, which result in continuous activation and signaling, dramatically altered the understanding and treatment of GISTs (3,4). Approximately 90% of GISTs are driven by gain-of-function mutations in one of the two type-III tyrosine kinase receptors. Although resection remains a principle therapy, tyrosine-kinase inhibitors have revolutionized the treatment of advanced and recurrent GISTs, allowing many patients with advanced disease to live many years and in some instances, obtain complete remission (5-8). Wild-type gastrointestinal stromal tumors (WT-GISTs) are defined as GISTs that lack the gain-of-function mutations in KIT and PDGFRA (9). Due to the different molecular drivers and the distinct tumor biology and behavior of these wild-type neoplasms, a different approach to treatment may be required when addressing these distinct GISTs. Epidemiology of WT-GIST Regardless of subtype, the incidence of all GISTs is approximately 14-20 per million population (1). The incidence of WT-GIST is as much as 10% of all GISTs (10). Patients with WT-GISTs usually present at a much younger

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Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs?

Cited by 8 publications

References 22 publications

Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report

Germline c.1A>C heterozygous pathogenic variant in SDHA reported for the first time in a young adult with a gastric gastrointestinal stromal tumour (GIST): a case report

Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors

Approach to wild-type gastrointestinal stromal tumors

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