Detection ofBRAF,NRAS,KIT,GNAQ,GNA11andMAP2K1/2mutations in Russian melanoma patients using LNA PCR clamp and biochip analysis

Emelyanova, Marina; Ghukasyan, L. G.; Абрамов, И. С.; Ryabaya, Oxana; Степанова, Е В; Kudryavtseva, Anna V.; Садритдинова, А. Ф.; Dzhumakova, Cholpon; Belysheva, T. S.; Surzhikov, Sergey A.; Lyubchenko, Lyudmila; Заседателев, А. С.; Nasedkina, T. V.

doi:10.18632/oncotarget.17014

Cited by 20 publications

(19 citation statements)

References 77 publications

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“…Another novel recurrent mutation identified in this study is in MAP2K1, which encodes MEK1. Although activating exonic mutations in the MAP2K1 gene have been reported (Emelyanova et al, ; Nikolaev et al, ), to our knowledge, there are no reports on MAP2K1 promoter mutations. Differential binding of transcription factors resulting from mutations in the promoter could affect MAP2K1 gene expression.…”

Section: Discussionmentioning

confidence: 84%

Functional analysis of RPS27 mutations and expression in melanoma

Floristán

Morales

Hanniford

et al. 2019

Pigment Cell Melanoma Res

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Next‐generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole‐genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27‐low patients displaying worse prognosis. In vitro characterization of RPS27‐high and RPS27‐low melanoma cell lines, as well as loss‐of‐function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27‐low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.

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Section: Discussionmentioning

confidence: 84%

Functional analysis of RPS27 mutations and expression in melanoma

Floristán

Morales

Hanniford

et al. 2019

Pigment Cell Melanoma Res

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“…In another study of 127 melanomas, eight had MAP2K1 point mutations and two had MAP2K2 point mutations [ 10 ]; these alterations were associated with constitutive ERK phosphorylation, and most co-occurred with either BRAF or NRAS mutation. Other series revealed MAP2K1 point mutations in two of 253 melanomas [ 29 ] and MAP2K1 mutations of unspecified type in 21 of 356 melanomas [ 30 ]. A case report of cutaneous melanoma metastases sampled over time revealed a MAP2K1 (F53Y) missense mutation paired with a BRAF fusion [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations

Williams¹,

Montesion²,

Shah³

et al. 2020

Modern Pathology

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While the genomics of BRAF, NRAS, and other key genes influencing MAP kinase (MAPK) activity have been thoroughly characterized in melanoma, mutations in MAP2K1 (MEK1) have received significantly less attention and have consisted almost entirely of missense mutations considered secondary oncogenic drivers of melanoma. Here, we investigated melanomas with in-frame deletions of MAP2K1, alterations characterized as MAPK-activating in recent experimental models. Our case archive of clinical melanoma samples with comprehensive genomic profiling by a hybrid capture-based DNA sequencing platform was searched for MAP2K1 genetic alterations. Clinical data, pathology reports, and histopathology were reviewed for each case. From a cohort of 7119 advanced melanomas, 37 unique cases (0.5%) featured small in-frame deletions in MAP2K1. These included E102_I103del (n = 11 cases), P105_A106del (n = 8), Q58_E62del (n = 6), I103_K104del (n = 5), I99_K104del (n = 3), L98_I103del (n = 3), and E41_F53del (n = 1). All 37 were wild type for BRAF, NRAS, and NF1 genomic alterations (“triple wild-type”), representing 2.0% of triple wild-type melanomas overall (37/1882). Median age was 66 years and 49% were male. The majority arose from primary cutaneous sites (35/37; 95%) and demonstrated a UV signature when available (21/25; 84%). Tumor mutational burden was typical for cutaneous melanoma (median = 9.6 mut/Mb, range 0–35.7), and frequently mutated genes included TERTp (63%), CDKN2A (46%), TP53 (11%), PTEN (8%), APC (8%), and CTNNB1 (5%). Histopathology revealed a spectrum of appearances typical of melanoma. For comparison, we evaluated 221 cases with pathogenic missense single nucleotide variants in MAP2K1. The vast majority of melanomas with missense SNVs in MAP2K1 showed co-mutations in BRAF (58%), NF1 (23%), or NRAS (18%). In-frame deletions in MAP2K1, previously shown in experimental models to be strongly MAPK-activating, characterized a significant subset of triple wild-type melanoma (2.0%), suggesting a primary oncogenic role for these mutations. Comprehensive genomic profiling of melanomas enables detection of this alteration, which may have implications for potential therapeutic options.

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“…Various mutations in the BRAF (51.0%), NRAS (17.8%), KIT (2.4%), GNAQ (1.6%), GNA11 (0.8%), and MAP2K1 genes have been revealed (0.8%). The approach allows one to efficiently detect clinically relevant somatic mutations and choose the optimal target drug in 70% of melanoma patients [47].…”

Section: Microarrays For Personalized Treatment Of Cancer Patientsmentioning

confidence: 99%

The EIMB Hydrogel Microarray Technology: Thirty Years Later

Gryadunov¹,

Shaskolskiy²,

Наседкина³

et al. 2018

Acta Naturae

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Biological microarrays (biochips) are analytical tools that can be used to implement complex integrative genomic and proteomic approaches to the solution of problems of personalized medicine (e.g., patient examination in order to reveal the disease long before the manifestation of clinical symptoms, assess the severity of pathological or infectious processes, and choose a rational treatment). The efficiency of biochips is predicated on their ability to perform multiple parallel specific reactions and to allow one to study the interactions of biopolymer molecules, such as DNA, proteins, glycans, etc. One of the pioneers of microarray technology was the Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences (EIMB), with its suggestion to immobilize molecular probes in the three-dimensional structure of a hydrophilic gel. Since the first experiments on sequencing by hybridization on oligonucleotide microarrays conducted some 30 years ago, the hydrogel microarrays designed at the EIMB have come a long and successful way from basic research to clinical laboratory diagnostics. This review discusses the key aspects of hydrogel microarray technology and a number of state-ofthe-art approaches for a multiplex analysis of DNA and the protein biomarkers of socially significant diseases, including the molecular genetic, immunological, and epidemiological aspects of pathogenesis. KEYWORDS hydrogel microarrays, nucleic acid hybridization, multiplex immunochemical assay, antimicrobial drug resistance, genotyping, tumor markers. ABBREVIATIONS NAs -nucleic acids; NGS -next-generation sequencing; FDA -Food and Drug Administration (USA); MTB -Mycobacterium tuberculosis, causative agent of tuberculosis; NTM -non-tuberculous mycobacteria, causative agents of mycobacteriosis; HCV -hepatitis C virus; RMP -rifampin; INH -isoniazid; EMBethambutol; MDR -multidrug resistance; XDR -extensive drug resistance; RTIs -reproductive tract infections; AMD -antimicrobial drugs; CRC -colorectal carcinoma; CEA -carcinoembryonic antigen; CA -carbohydrate antigen. REVIEWS VOL. 10 № 4 (39) 2018 | ACTA NATURAE | 5

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Detection ofBRAF,NRAS,KIT,GNAQ,GNA11andMAP2K1/2mutations in Russian melanoma patients using LNA PCR clamp and biochip analysis

Cited by 20 publications

References 77 publications

Functional analysis of RPS27 mutations and expression in melanoma

Functional analysis of RPS27 mutations and expression in melanoma

Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations

The EIMB Hydrogel Microarray Technology: Thirty Years Later

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