A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants

Tichá, Ivana; Hojný, J.; Michálková, Romana; Kodet, Ondřej; Krkavcová, Eva; Hájková, Nikola; Němejcová, Kristýna; Bártů, Michaela; Jakša, Radek; Důra, Miroslav; Kanwal, Madiha; Martinikova, Andra S.; Macůrek, Libor; Zemánková, Petra; Kleibl, Zdeněk; Dundr, Pavel

doi:10.1038/s41598-019-53636-x

Cited by 36 publications

(36 citation statements)

References 56 publications

(73 reference statements)

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“…Mutations in nine genes encoding for subunits of the SWI/SNF chromatin remodeling complex are found in 20.0% of human cancers (Shain and Pollack, 2013). ARID2 was found frequently mutated in melanoma, with a frequency ranging from 7.0 to 18.0% (Hodis et al, 2012;Krauthammer et al, 2012;Ticha et al, 2019). In our dataset, mutations and CNVs in ARID2 are found in 12.9 and 5.5%, respectively, as shown in Figures 2, 3 and Supplementary Figure S2C.…”

Section: Arid2supporting

confidence: 57%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.

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Section: Arid2supporting

confidence: 57%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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“…DNA from 5-10 tissue sections (5 µm) from the archived FFPE tissue blocks was isolated using an automatic isolator MagCore Nucleic Acid Extractor, utilizing the MagCore Genomic DNA FFPE One-step kit, Ref MGF-03 (RBC Bioscience). The isolated DNA was quantified by Qubit fluorimeter (Thermo Fisher) and underwent a quality control test of amplification efficacy by qPCR (5 ng of the DNA sample was amplified using 5 × HOT FIREPol EvaGreen HRM Mix NO ROX; Solis Biodyne) as we described elsewhere 66 . Only the samples which passed the quality criteria (Cp < 35 for a 180 bp product amplification; 24/46 samples) were used for the subsequent analysis.…”

Section: Samplesmentioning

confidence: 99%

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

Dundr

Bártů

Hojný

et al. 2020

Sci Rep

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Hepatocyte nuclear factor 1 beta (HNF1B) is a tissue specific transcription factor, which seems to play an important role in the carcinogenesis of several tumors. In our study we focused on analyzing HNF1B in prostate carcinoma (PC) and adenomyomatous hyperplasia (AH), as well as its possible relation to the upstream gene EZH2 and downstream gene ECI2. The results of our study showed that on an immunohistochemical level, the expression of HNF1B was low in PC, did not differ between PC and AH, and did not correlate with any clinical outcomes. In PC, mutations of HNF1B gene were rare, but the methylation of its promotor was a common finding and was positively correlated with Gleason score and stage. The relationship between HNF1B and EZH2/ECI2 was equivocal, but EZH2 and ECI2 were positively correlated on both mRNA and protein level. The expression of EZH2 was associated with poor prognosis. ECI2 did not correlate with any clinical outcomes. Our results support the oncosuppressive role of HNF1B in PC, which may be silenced by promotor methylation and other mechanisms, but not by gene mutation. The high expression of EZH2 (especially) and ECI2 in PC seems to be a potential therapeutic target. Hepatocyte nuclear factor 1 beta (HNF1B) is an important tissue specific transcription factor, which is essential for the embryonic development of several organs including the kidney, pancreas, liver, biliary tract, genital tract, and gastrointestinal system 1,2. Heterozygous germline mutations are associated with several congenital diseases of the kidney, pancreas, and urogenital tract, and the role of HNF1B in these diseases is well known 3-5. However, despite the increased awareness that HNF1B plays an important role in the carcinogenesis of several solid tumors, the exact significance of HNF1B in carcinogenesis is not yet fully understood 6-9. The regulatory mechanisms and pathways in which HNF1B is involved in the process of carcinogenesis are not clear, but it appears that HNF1B may act as either oncogene or oncosuppressor gene based on the type of tumor and its histogenesis 6,7,10. In the prostate, an increased expression of HNF1B seems to be protective against prostate cancer, and HNF1B therefore has been attributed an oncosuppressive role 10. However, the levels of protein expression of HNF1B in prostate cancer are not well known, and the mechanisms playing role in its regulation are of interest. According to current knowledge, HNF1B is commonly inactivated in prostate cancer, especially due to HNF1B promoter methylation, which occurs in about 50% of cases 11. Another recently suggested possible mechanisms of HNF1B inactivation is the effect of the enhancer of zeste homolog 2 (EZH2), the overexpression of which has been suggested to downregulate the expression of HNF1B 12,13. EZH2 is a gene belonging to the category of Polycomb

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“…Both of these substitutions are described for the first time not only in spinal cord astrocytomas, but also in CNS tumors in general. We were able to find only two publications where the first mutation (R82K) was described in patients with acute myeloid leukemia [ 11 ] and primary skin melanoma [ 12 ]. We did not find data on the second mutation (I76T).…”

Section: Resultsmentioning

confidence: 99%

Rare Cases of IDH1 Mutations in Spinal Cord Astrocytomas

et al. 2020

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A low occurrence rate of spinal cord gliomas (4.3% of primary and glial CNS tumors) and the associated difficulties in building statistically significant cohorts of patients considerably slow down the development of effective approaches to the treatment of spinal cord tumors compared to brain tumors. Despite our extensiveknowledge regardingIDHmutations in intracranial tumors, mutations of this gene in spinal cord astrocytomas remain poorly understood. In thisstudy, we report on five cases of identified mutations in theIDH1gene in spinal cord astrocytoma cells, two of which are unique, as they have never been previously described in CNS gliomas.

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A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants

Cited by 36 publications

References 56 publications

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

HNF1B, EZH2 and ECI2 in prostate carcinoma. Molecular, immunohistochemical and clinico-pathological study

Rare Cases of IDH1 Mutations in Spinal Cord Astrocytomas

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