Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors

Jašek, Karin; Buzalkova, V; Minárik, Gabriel; Stanclova, Andrea; Szépe, P; Lasabová, Zora

doi:10.1007/s00428-016-2044-4

Cited by 23 publications

(25 citation statements)

References 30 publications

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“…In contrast Shitara et al found no mutations in RAC1, PPP6C, STK19 genes in melanomas associated with intermittent sun-exposed melanomas [23]. Further, our results indicate that allele-specific PCR is more sensitive than Sanger sequencing [19,24], so we used allele-specific PCR to detect BRAF V600E mutation. We performed allele-specific PCR only on BRAF, because it had already been applied by Jasek et al [19].…”

Section: Discussioncontrasting

confidence: 61%

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Detection of driver mutations in FFPE samples from patients with verified malignant melanoma

Malicherova¹,

Burjanivová²,

Minarikova³

et al. 2019

neo

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Malignant melanoma is an oncological disease characterized by etiologic heterogeneity and it has increasing incidence and mortality in the Slovak Republic. While it is treated surgically in combination with chemotherapy, targeted therapy, and immunotherapy, malignant melanomas can ulcerate and are susceptible to infections. These are highly aggressive cancers with metastasis, and recent studies have shown the presence of mutations in RAC1, PPP6C and STK19 genes in melanoma patients. Mutations in these genes are driver mutations; important in oncogenesis and providing selective advantage to tumor cells. The aim of our study is to establish a method to detect driver mutations in formalin-fixed, paraffin embedded (FFPE) tissue DNA. We applied Sanger sequencing to detect driver somatic mutations in RAC1, PPP6C, STK19 and BRAF genes in patients with malignant melanoma. Confirmation of BRAF V600E mutation was obtained by allele-specific PCR. The BRAF V600E mutation was present in 15 of 113 patients (13.2%) and the driver mutation in 7 of 113 patients (6.2 %). Our results demonstrate that Sanger sequencing analysis detects mutations in FFPE clinical samples. The identification of these somatic driver mutations in samples with verified malignant melanomas enabled development of a molecular classification of melanomas, and our study provides evidence of diversity of novel driver mutations implicated in malignant melanoma pathogenesis. These findings could have very important implications for targeted therapy.

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Section: Discussioncontrasting

confidence: 61%

“…We used allele-specific PCR for confirmation of V600E mutation in the BRAF gene. This assay was previously established in our laboratory and the allele-specific PCR for the BRAF V600E mutation was adopted from Jasek et al [19].…”

Section: Methodsmentioning

confidence: 99%

Detection of driver mutations in FFPE samples from patients with verified malignant melanoma

Malicherova¹,

Burjanivová²,

Minarikova³

et al. 2019

neo

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“…The subgroup of the remaining KIT/PDGFRA WT GIST, but not SDH- deficient , have been further characterized: 4–13% carry a BRAF V600E mutation, are localized more frequently in small intestine and seem to have a more favourable prognosis [18–21]. Within the not SDH- deficient , some GIST have a neurofibromatosis (NF) type 1 mutation and show a female prevalence, a frequent non-gastric site and multifocal localization often unveiling an unrecognized NF1 syndromic condition [22–26].…”

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confidence: 99%

The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST)

et al. 2017

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Recent advances in molecular biology have revolutionized the concept of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumors (GIST) than the past. Indeed, from being defined as GIST without KIT or PDGFRA mutations, we are now faced with the opposite scenario, where KIT/PDGFRA WT GIST are “positively” defined according to their specific molecular alterations. In particular, if until recently KIT/PDGFRA GIST without abnormalities of KIT, PDGFRA, SDH, and the RAS signaling pathway were referred as quadruple WT GIST, today also this small subset of GIST is emerging out as a group of heterogeneous distinct entities with multiple different molecular alterations. Therefore, given this still growing and rapidly evolving scenario, the progressive molecular fragmentation may inevitably lead over the time to the disappearance of KIT/PDGFRA WT GIST, destined to be singularly defined by their molecular fingerprint.

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“…Following reported thermal conditions and primer pairs [28], BRAF gene was only sequenced for 22 GISTs retaining the wild-type KIT and PDGFRA genes, given that the concurrence of BRAF mutation with either KIT or PDGFRA mutation is extraordinary rare, if any, in GISTs [29, 30]. In fact, all these 22 cases revealed no mutation in the hotspot exon 15 that encompasses codon Val600 (Supplementary Figure 1A).…”

Section: Methodsmentioning

confidence: 99%

PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival

Liu

Chuang

et al. 2017

Oncotarget

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To explore the implications of lipid catabolism-associated genes in gastrointestinal stromal tumors, we reappraised transcriptomic and genomic datasets and identified copy-gained and differentially upregulated PLCB4 gene associated with tumor progression. On full sections, PLCB4 mRNA abundance and PLCß4 immunoexpression were validated in 70 cases. On tissue microarrays, PLCB4 gene copies and PLCß4 immunoexpression were both informative in 350 cases with KIT/PDGFRA/BRAF genotypes noted in 213. In GIST48 cell line, we stably silenced PLCB4 and YAP1 to characterize their functional effects and regulatory link. Compared with normal tissue, PLCB4 mRNA abundance significantly increased across tumors of various risk levels (p<0.001), and was strongly correlated with immunoexpression level (p<0.001, r=0.468). Including polysomy (12.6%) and amplification (17.4%), PLCB4 copy gain was detected in 105 (30%) cases and significantly more frequent (p<0.001) in cases exhibiting higher PLCß4 immunoexpression (82/175). Copy gain and protein overexpression were modestly associated with unfavorable genotypes (both p<0.05), strongly associated with increased size, mitosis, and risk levels defined by both the NIH and NCCN schemes (all p<0.001), and univariately predictive of shorter disease-free survival (both p<0.0001). In PLCß4-overexpressing cases, PLCB4 copy gain still predicted worse prognosis (p<0.0001). In a multivariate comparison, both overexpression (p=0.007, hazard ratio: 2.454) and copy gain (p=0.031, hazard ratio: 1.892) exhibited independent impact. In vitro, YAP1 increased PLCB4 mRNA and protein expression, and both molecules significantly promoted cell proliferation. Being driven by copy gain or YAP1, PLCß4 is a novel overexpressed enzyme regulating lipid catabolism that promotes cell proliferation and independently confers a worse prognosis.

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Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors

Cited by 23 publications

References 30 publications

Detection of driver mutations in FFPE samples from patients with verified malignant melanoma

Detection of driver mutations in FFPE samples from patients with verified malignant melanoma

The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST)

PLCB4 copy gain and PLCß4 overexpression in primary gastrointestinal stromal tumors: Integrative characterization of a lipid-catabolizing enzyme associated with worse disease-free survival

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