An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

Nannini, Margherita; Biasco, Guido; Astolfi, Annalisa; Pantaleo, Maria Abbondanza

doi:10.1136/jmedgenet-2013-101695

Cited by 79 publications

(77 citation statements)

References 81 publications

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“…Despite the fact that this latter tumor type has never been associated with SDH deficiency, we showed loss of SDHB expression in one of the aforementioned ACCs, but without any germline SDH-x pathogenic mutations or gross deletions detected. This finding further extends the spectrum of tumors displaying loss of SDHB and/or SDHA expression in the absence of causative SDH-x mutations, including a clinicopathologically and biologically distinctive subset of KIT/PDGFRA WT GISTs (Barletta & Hornick 2012, Nannini et al 2013, poorly and/or un-differentiated NBLs (Feichtinger et al 2010), and a clear cell RCC with sarcomatous dedifferentiation (Papathomas et al 2013).…”

Section: Discussionmentioning

confidence: 95%

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Papathomas¹,

Oudijk²,

Zwarthoff³

et al. 2014

Endocrine-Related Cancer

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Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (PZ0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact

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Section: Discussionmentioning

confidence: 95%

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Papathomas¹,

Oudijk²,

Zwarthoff³

et al. 2014

Endocrine-Related Cancer

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“…In particular, it has been shown that deletions of KIT exon 11, especially those involving codon 557 and/or codon 558 (designated as KITdel-inc557/558), are associated with malignant behavior (11)(12)(13)(14). Conversely, KIT/PDGFRA WT GIST and most PDGFRA-mutated GIST generally have a lower potential for malignancy (2,15). However, the available data are still insufficient to be incorporated into routine clinical risk assessment.…”

Section: Introductionmentioning

confidence: 99%

“…Approximately 10% to 15% of adult GIST and 85% of pediatric GIST, defined as KIT/PDGFRA "wild type" (WT), lack KIT or PDGFRA mutations. These tumors are highly heterogeneous and profoundly different from KIT/PDGFRA-mutated GIST in terms of clinical behavior and molecular profiles, and they are now considered as separate pathologic entities (2).…”

Section: Introductionmentioning

confidence: 99%

Tumor Genotype Is an Independent Prognostic Factor in Primary Gastrointestinal Stromal Tumors of Gastric Origin: A European Multicenter Analysis Based on ConticaGIST

Woźniak

Rutkowski

Schöffski

et al. 2014

Clinical Cancer Research

142

112

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Purpose: Although the mutational status in gastrointestinal stromal tumors (GIST) can predict the response to treatment with tyrosine kinase inhibitors, the role of tumor genotype as a prognostic factor remains controversial. The ConticaGIST study sought to determine the pathologic and molecular factors associated with disease-free survival (DFS) in patients with operable, imatinib-naive GIST.Experimental Design: Clinicopathologic and molecular data from 1,056 patients with localized GIST who underwent surgery with curative intention (R0/R1) and were registered in the European ConticaGIST database were prospectively obtained and reviewed. Risk of tumor recurrence was stratified using the modified NIH criteria. The median follow-up was 52 months.Results: On testing for potential prognostic parameters, the following were associated with inferior DFS on multivariable Cox model analysis: primary nongastric site, size >10 cm, mitotic index >10 mitoses per 50 high power field, and the KIT exon 9 duplication [hazard ratio (HR), 1.47; 95% confidence interval (CI), 0.9-2.5; P ¼ 0.037] and KIT exon 11 deletions involving codons 557 and/or 558 [KITdel-inc557/558; HR, 1.45; 95% CI, 1.0-2.2; P ¼ 0.004]. Conversely, PDGFRA exon 18 mutations were indicators of better prognosis [HR, 0.23; 95% CI, 0.1-0.6; P ¼ 0.002]. KITdel-inc557/558 were an adverse indicator only in GIST localized in the stomach (P < 0.001) but not in tumors with nongastric origin. In gastric GIST, all other mutations presented remarkably superior 5-year DFS.Conclusions: In conclusion, tumor genotype is an independent molecular prognostic variable associated with gastric GIST and should be used for optimizing tailored adjuvant imatinib treatment.

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“…[68][69][70] The extent of surgery should be determined on a case-by-case basis, taking into account the risk of recurrence, the lack of benefit from available tyrosine kinase inhibitors, and the actual behavior of the underlying disease.…”

Section: Gastrointestinal Stromal Tumorsmentioning

confidence: 99%

Surgical management of localized soft tissue tumors

Gronchi

Colombo

Raut

2014

Cancer

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Soft tissue tumors are rare and can arise from a variety of soft tissues and viscera in a variety of body sites. Their management requires a thorough understanding of the biology of the different histologies and molecular subtypes as well as the constraints of specific anatomic sites. The surgical approach has undergone significant changes thanks to a better understanding of the natural history of the different histologic subtypes, the importance of site, and the different sensitivity to available drugs. The soft tissue tumor family includes 3 major, distinct categories: desmoid-type fibromatosis, soft tissue sarcoma, and gastrointestinal stromal tumor. In general, limb-sparing and function-sparing approaches should be used when feasible for tumors located in the extremities and girdles. Resections of adherent structures/viscera, which may be close but not invaded, may be needed in tumors arising in the retroperitoneum/abdomen to minimize microscopic intralesional margins, maximize local tumor control, and possibly improve survival. Margins of resection and the use of adjuvant/neadjuvant radiation therapy and/or chemotherapy are contingent on an accurate histologic diagnosis. Treatment planning should include multidisciplinary consultation to determine optimal therapy, taking into consideration tumor histology, site and extent of the disease, its natural history and sensitivity to available treatments, surgical challenges, and-of course-quality of life. Cancer 2014;120:2638-48.

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An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

Cited by 79 publications

References 81 publications

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia

Tumor Genotype Is an Independent Prognostic Factor in Primary Gastrointestinal Stromal Tumors of Gastric Origin: A European Multicenter Analysis Based on ConticaGIST

Surgical management of localized soft tissue tumors

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