Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “NRAS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources
PubMed2026

DNA Methylation Profiling of Pediatric Ectomesenchymoma Supports Embryonal Rhabdomyosarcoma-Like Epigenetic Identity.

Ectomesenchymoma is a rare, biphenotypic pediatric tumor combining rhabdomyoblastic and neuroectodermal differentiation. We characterize two novel cases through integrated genomics and the first report of genome-wide DNA methylation profiling. Both tumors harbored RAS-pathway mutations (HRAS p.Gly13Arg; NRAS p.Gln61His). Methylation analysis, including microdissected components, consistently aligned ectomesenchymoma with the embryonal rhabdomyosarcoma superfamily, revealing a shared myogenic epigenetic program despite neural differentiation. Shared copy-number profiles across distinct histological regions supported a monoclonal origin. Overall, our data support a close biological relationship between ectomesenchymoma and embryonal rhabdomyosarcoma and indicate that RAS-pathway testing and methylation profiling can significantly refine diagnostic precision.

Humans↗
PubMed2026

Genomic Characterization of ETV6::RUNX1-Positive Childhood B-ALL in a Chinese Cohort: Novel Fusion Partners, Co-Occurring Mutations, and Risk-Stratifying Biomarkers.

BACKGROUND: ETV6::RUNX1 is the most common genetic abnormality in pediatric B-cell acute lymphoblastic leukemia (ALL; ∼25%), yet the comprehensive genetic architecture and molecular predictors of intermediate-risk (IR) stratification remain incompletely characterized. METHODS: We performed whole-transcriptome sequencing (Illumina NovaSeq 6000, rRNA depletion, 41.70 Gb/sample) on bone marrow samples from 93 pediatric ETV6::RUNX1-positive B-ALL patients. Bioinformatics analysis included STAR alignment, MuTect2 variant calling, FusionCatcher fusion detection, and VEP annotation. The Jaccard index with permutation testing assessed mutation co-occurrence; logistic regression identified independent predictors of IR classification. RESULTS: Beyond ETV6::RUNX1, we identified 51 distinct fusion genes across the cohort, including the reciprocal RUNX1-ETV6 (73.1%), chr8::KLF1210 (38.7%), and KLF12-chr8 (34.4%). Somatic mutations in 249 genes were detected; the most frequent were KIAA1715 (17.2%), KRAS (11.8%), and NSD2 (10.8%). Network analysis revealed significant chromatin modifier co-occurrence (KIAA1715-KMT2C: J = 0.136, p = 0.015) and KRAS-NRAS mutual exclusivity (J = 0.000, p = 0.042). PTCH1 (OR = 3.50, 95% CI 0.21-58.49, p = 0.41) and GNB1 (OR = 6.5, 95% CI 1.2-34.8, p = 0.029) mutations independently predicted IR classification. chr8::KLF1210 fusion correlated with higher Day-19 MRD levels (p = 0.038). CONCLUSIONS: GNB1 mutation represents a novel independent predictor of IR stratification in ETV6::RUNX1-positive B-ALL. The chromatin modifier co-occurrence module and extensive fusion architecture reveal biological heterogeneity within this favorable-risk subtype, with potential implications for risk-adapted therapeutic strategies.

B‐ALL↗
PubMed2005

Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. In the current study, genetic alterations in a panel of ATC were profiled to determine the origins of ATC. METHODS: Eight ATC were analyzed for BRAF mutation at codon 599 by using mutant-allele-specific polymerase chain reaction (PCR) and DNA sequencing of the PCR-amplified exon 15. RAS mutation (HRAS, KRAS, and NRAS) at codons 12, 13, and 61 was analyzed by direct sequencing of PCR-amplified exons 1 and 2 of the RAS gene. RET/PTC rearrangements and p53 mutation were monitored by immunohistochemical (IHC) staining by anti-RET antibodies and an anti-p53 mAb, respectively. RESULTS: BRAF was mutated in 5 of the 8 ATCs tested. Histologic examination revealed that 4 of these 5 BRAF-mutated ATCs contained a PTC component, suggesting that they may be derived from BRAF-mutated PTC. Of the 3 ATCs with wild-type BRAF, 2 had spindle cell features; one had follicular neoplastic characteristics mixed with papillary structures. Analysis of RAS mutation revealed only an HRAS mutation at codon 11, due to the transversion of GCC to TCC in one ATC with wild-type BRAF. This leads to the substitution of valine to serine. IHC analysis of RET/PTC rearrangements revealed no positive staining of RET in any of 8 ATCs, suggesting that these ATCs are not derived from RET/PTC- rearranged PTC. In contrast, IHC analysis of p53 mutation revealed that p53 was detected in the nuclei of 5 of 5 BRAF-mutated ATCs and 2 of 3 ATCs with wild-type BRAF. p53 staining was present only in anaplastic thyroid tumor cells but not in neighboring papillary thyroid tumor cells. CONCLUSIONS: These results suggest that many ATCs with papillary components are derived from BRAF-mutated PTC, because of the addition of p53 mutation.

Aged↗
PubMed2003

Genetic alterations in primary cutaneous CD30+ anaplastic large cell lymphoma.

Primary cutaneous CD30+ anaplastic large cell lymphoma (C-ALCL) represents a distinct clinical subtype of CD30+ anaplastic large cell lymphomas. The etiology and underlying molecular pathogenesis of C-ALCL remain unclear. This study aimed to investigate genetic changes in C-ALCL. Comparative genomic hybridization (CGH) analysis of 23 DNA samples from 15 C-ALCL cases identified chromosome imbalances (CI) in 10 samples from eight cases (43%). The mean number of CI per sample was 2.09 +/- 3.86, with gains (2.00 +/- 3.85) more common than losses (0.09 +/- 0.29). The most frequent CI were gains of 1/1p and 5 (50%) and 6, 7, 8/8p, and 19 (38%). Microarray-based CGH analysis of six DNA samples from five cases with CI revealed genomic imbalances (GI) in all of the cases studied. This included oncogene copy number gains of FGFR1 (8p11) in three cases, and NRAS (1p13.2), MYCN (2p24.1), RAF1 (3p25), CTSB (8p22), FES (15q26.1), and CBFA2 (21q22.3) in two cases. Real-time PCR analysis of nine DNA samples from eight cases with CI and GI detected amplifications of CTSB and RAF1 in seven cases (88%), REL (2p13p12) and JUNB (19p13.2) in six cases (75%), and MYCN and YES1 (18p11.3) in four cases (50%). Immunohistochemical staining of paraffin sections from six cases demonstrated expression of JUNB protein in five cases and BCL2 in three cases. These results reveal a consistent pattern of genetic alterations in C-ALCL and provide the molecular basis for further investigation of this disease.

Chromosome Aberrations↗
PubMed2004

RAS, FLT3, and TP53 mutations in therapy-related myeloid malignancies with abnormalities of chromosomes 5 and 7.

Oncogenic mutations in the KRAS2, NRAS, or FLT3 gene are detected in more than 50% of patients with de novo acute myeloid leukemia (AML). RAS mutations are also prevalent in de novo myelodysplastic syndrome (MDS), especially chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia. However, few studies have examined these genetic lesions in therapy-related myeloid malignancies. Monosomy 7/del(7q) and monosomy 5/del(5q) represent the most common cytogenetic abnormalities in therapy-related MDS and AML (t-MDS/t-AML) and are strongly associated with prior exposure to alkylating agents. Mutational analysis of bone marrow specimens from a well-characterized cohort of 26 t-MDS/t-AML patients with abnormalities of chromosomes 5 and/or 7 revealed 3 with RAS mutations. Further analyses of 23 of these cases uncovered one FLT3 internal tandem duplication and five TP53 mutations. The four patients with RAS or FLT3 mutations had monosomy 7, including one with abnormalities of chromosomes 5 and 7. One specimen demonstrated mutations in both KRAS2 and TP53. RAS and FLT3 mutations, which are thought to stimulate the proliferation of leukemia cells, appear to be less common in t-MDS/t-AML than in de novo AML, whereas TP53 mutations are more frequent.

Acute Disease↗
PubMed2006

Transient response to imatinib in a chronic eosinophilic leukemia associated with ins(9;4)(q33;q12q25) and a CDK5RAP2-PDGFRA fusion gene.

Chronic myeloproliferative disorders with rearrangements of the platelet-derived growth factor receptor A (PDGFRA) gene at chromosome band 4q12 have shown excellent responses to targeted therapy with imatinib. Here we report a female patient who presented with advanced phase of a chronic eosinophilic leukemia. Cytogenetic analysis revealed an ins(9;4)(q33;q12q25) in 5 of 21 metaphases. FISH analysis with flanking BAC probes indicated that PDGFRA was disrupted. A novel mRNA in-frame fusion between exon 13 of the CDK5 regulatory subunit associated protein 2 (CDK5RAP2) gene, a 40-bp insert that was partially derived from an inverted sequence stretch of PDGFRA intron 9, and a truncated PDGFRA exon 12 was identified by 5'-RACE-PCR. CDK5RAP2 encodes a protein that is believed to be involved in centrosomal regulation. The predicted CDK5RAP2-PDGFRA protein consists of 1,003 amino acids and retains both tyrosine kinase domains of PDGFRA and several potential dimerization domains of CDK5RAP2. Despite achieving complete cytogenetic and molecular remission on imatinib, the patient relapsed with imatinib-resistant acute myeloid leukemia that was characterized by a normal karyotype, absence of detectable CDK5RAP2-PDGFRA mRNA, and a newly acquired G12D NRAS mutation.

Aged↗
PubMed1990

Frequent rearrangement of chromosomal bands 1p22 and 11q13 in squamous cell carcinomas of the head and neck.

We report the finding of clonal structural chromosome abnormalities in short-term cultures from 15 squamous cell carcinomas of the head and neck region. When the distribution of chromosomal breakpoints in these 15 tumors and in the 16 head and neck carcinomas previously described are assessed, a marked clustering is seen at bands 1p22 and 11q13, which are rearranged in eight and nine tumors, respectively. No other band was involved in aberrations in more than five tumors. Cytogenetic evidence of gene amplification was seen in four tumors, three times in the form of homogeneously staining regions (twice located in 11q13), and in one tumor as double minutes. Among the candidate genes for such amplification are BCLI, INT2, and HSTI, all of which map to 11q13, and NRAS, which maps to 1p22. All these oncogenes have previously been shown to be amplified in subsets of head and neck carcinomas. We conclude that bands 1p22 and 11q13 are nonrandomly involved in chromosomal rearrangements in head and neck carcinomas and suggest that activation of oncogenes located in these bands may proceed via cytogenetic mechanisms.

Aged↗
PubMed1992

Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization.

Preliminary studies of RAS mutational activation in human testicular germ cell neoplasms have yielded conflicting results. Whereas two studies of clinical material revealed a significant incidence of N- and KRAS mutations, two studies of a variety of germ cell lines failed to document RAS mutations. To clarify the incidence of RAS mutations in these tumors, we studied archival paraffin-embedded, formalin-fixed orchiectomy specimens from 25 nonseminomas (NSGCT), 18 seminomas (SEM), and one Leydig cell tumor. For 14 of the 44 neoplasms, DNA was also available from nonmalignant testis adjacent to the tumor. Six age-matched patients had testes removed because of nonmalignant disease and were studied as controls. Polymerase chain reaction (PCR) amplified the K-, N-, and HRAS 12, 13, and 61 codons of these specimens, and mutations were detected with mutation-specific oligonucleotide probe hybridization of Southern and slot blots. Four mutations were found in KRAS 12 (4/44;[9.1%]). One seminoma [1/18(5.6%)] contained the mutation GGT(GLY)----CGT(ARG), and three NSGCT [3/25(12%)] were found to have GGT(GLY)----GAT(ASP) mutations. One of the NSGCT mutations was detected in adjacent nonmalignant tissue, but the corresponding tumor did not contain any detectable mutation. No mutations were detected at KRAS 13 or 61, in NRAS or HRAS 12, 13, or 61, or in the control normal testes. PCR, slot blots, and hybridizations were performed twice by two separate investigators for confirmation of results. PCR-generated mutation-specific positive controls were created for all possible RAS mutations, and these along with wild-type DNA controls were integral to interpretation of the oligonucleotide mismatch hybridization assay. By using positive and negative controls, we have detected a relatively low incidence of RAS mutations in archival human testicular germ cell tumors.

Blotting, Southern↗
PubMed1995

N- and KRAS mutations in primary testicular germ cell tumors: incidence and possible biological implications.

Recently, conflicting results have been reported on the incidence of RAS mutations in primary testicular germ cell tumors of adults (TGCTs). In four studies a low incidence of mutations (less than 15%) in a variety of TGCTs or derived cell lines was found, whereas in two other studies a high incidence of N- or KRAS mutations (over 40%) was shown. A total of 62 testicular seminomas (SE) and 34 nonseminomatous TGCTs (NS) were studied thus far. The largest series consisted of 42 TGCTs, studied on paraffin embedded tissue. We present the results of analysis for the presence of N- and KRAS mutations, in codons 12, 13, and 61, in snap frozen samples of 100 primary TGCTs, comprising 40 SE and 60 NS. Using the polymerase chain reaction (PCR) and allele specific oligonucleotide hybridization (ASO), mutations were found in five SE (three in NRAS and two in KRAS, all codon 12), and in one NS (KRAS, codon 12). To exclude underestimation of the incidence of RAS mutations in TGCTs due to the presence of an excess of wild type alleles in the analyzed sample, a PCR technique preferentially amplifying KRAS alleles with a mutation in codon 12 was applied to all SE. This approach, allowing a 250 times more sensitive assay, resulted in the detection of only one additional SE with a mutation. Based on a critical analysis of published data and on our results from the largest series of frozen samples investigated thus far, we conclude that N- or KRAS mutations are rare and apparently not essential for initiation or progression of TGCTs.

Alleles↗
PubMed2007

Oncogenic KRAS provides a uniquely powerful and variable oncogenic contribution among RAS family members in the colonic epithelium.

Activating mutations of the RAS family of small GTPases are among the most common genetic events in human tumorigenesis. Constitutive activation of the three canonical family members, KRAS, NRAS, and HRAS segregate strongly by tissue type. Of these, KRAS mutations predominate in human tumors, including those arising from the colon and lung. We sought to compare the oncogenic contributions of different RAS isoforms in a comparable genetic setting and to explore downstream molecular changes that may explain the apparent differential oncogenic effects of the various RAS family members. We utilized colorectal cancer cell lines characterized by oncogenic KRAS in parallel with isogenically derived lines in which the mutant allele has been disrupted. We additionally attempted to reconstitute the isogenic derivatives with oncogenic forms of other RAS family members and analyze them in parallel. Pairwise analysis of HCT 116 and DLD-1 cell lines as well as their isogenic derivatives reveals distinct K-RAS(G13D) signatures despite the genetic similarities of these cell lines. In DLD-1, for example, oncogenic K-RAS enhances the motility of these cells by downregulation of Rap1 activity, yet is not associated with increased ERK1/2 phosphorylation. In HCT 116, however, ERK1/2 phosphorylation is elevated relative to the isogenic derivative, but Rap1 activity is unchanged. K-RAS is uniquely oncogenic in the colonic epithelium, though the molecular aspects of its oncogenic contribution are not necessarily conserved across cell lines. We therefore conclude that the oncogenic contribution of K-RAS is a function of its multifaceted functionality and is highly context-dependent.

Cell Line, Tumor↗
PubMedDate not supplied

Cellular and molecular biology of melanoma.

Melanoma cells have surface markers that are expressed differently than in normal melanocytes and nevus cells. Monoclonal antibodies may define a phenotypic map of the various melanocytic lesions and can be used in immunohistopathology and immunoscintigraphy. Monoclonal antibodies directed against melanoma-associated glycoproteins and glycolipids are being tested for therapy. Rearrangements or deletions on chromosome 1, 6, and 7 are the most frequently observed cytogenetic abnormalities. Molecular studies have not given a clear picture. A subset of HRAS alleles has been reported to be associated with melanoma. NRAS activation by point mutation has been found in one fourth of the cases. Allele losses at different loci have been reported. Genetic linkage studies have given conflicting results on the presence of a gene for the melanoma-dysplastic nevus syndrome on the short arm of chromosome 1.

Antigens, Neoplasm↗
PubMed1992

Organization and chromosomal locations of Rap1a/Krev sequences in the mouse.

The human RAP1A gene encodes a protein that apparently can antagonize the function of oncogenic ras genes in gene transfer experiments, but its normal function is unknown. To understand the function of this gene, we have undertaken a study of the mouse homolog, Rap1a. The complete coding sequence of a mouse Rap1a cDNA has been determined, and genomic clones representing three distinct Rap1a species were recovered. We find that Rap1a is located on distal mouse Chromosome (Chr) 3 near Nras, Ampd-1, Tshb, Ngfb, and Atp1a1. Two related sequences (Rap1a-rs1 and Rap1a-rs2) were also characterized. Rap1a-rs1, which was not localized, has a sequence very similar to the Rap1a cDNA, suggesting that it has been recently acquired by the mouse genome. Rap1a-rs2 is more distantly related to the gene sequence and is located on Chr 2 near Actc-1.

Amino Acid Sequence↗
PubMed1986

Cell-surface antigens determined by human chromosomes 1 and 12: comparative serological and somatic cell genetic analysis of eight antigenic systems.

We have previously assigned several genes controlling expression of cell-surface antigens to human chromosomes 1 and 12. In the present study, we characterize three additional cell-surface antigens determined by these chromosomes. Two monoclonal antibodies, AbSR75 and AbMG6, define antigens expressed on a wide range of cultured human cells. In contrast, AbK66 defines an antigen with a more restricted distribution which is expressed on normal and malignant human epithelial cells but not on neuroectoderm-derived cells or hematopoietic cells. Normal adult fibroblasts are K66-, whereas fetal fibroblasts are K66+. Serological analysis of rodent-human hybrid cells permitted the assignment of MSK31, controlling SR75, and MSK32, controlling K66, to chromosome 1, whereas MSK27, controlling MG6, maps to chromosome 12. Analysis of hybrids containing only deleted copies of chromosome 1 or chromosome 12 established regional assignments for MSK31, MSK32, and MSK27 and also for the previously defined genes MSK1, MSK4, and MSK7. The MSK1 gene, coding for a 140,000 mol wt cell surface glycoprotein, was found to map to the same band (1p22) as the NRAS protooncogene and the gene encoding the beta-subunit of nerve growth factor (NGFB).

Animals↗
PubMed1986

Mapping thyrotropin beta subunit gene in man and mouse.

Thyrotropin (TSH) is composed of two subunits: alpha and beta. Previously, we have mapped the TSH alpha gene to human chromosome 6 and mouse chromosome 4. In this study we have located the human TSH beta gene on chromosome 1 and the mouse TSH beta gene to chromosome 3. These data suggest that the TSH beta gene lies in a conserved linkage group with the genes for amylase 1 and 2, nerve growth factor, and the protooncogene Nras.

Animals↗
PubMed2006

High-resolution mapping of molecular events associated with immortalization, transformation, and progression to breast cancer in the MCF10 model.

BACKGROUND: A comprehensive and consistent picture of the genetic changes that underlie breast cancer initiation, development, and progression remains unresolved. The MCF10 series of cell lines represents many steps in that progression. We performed high resolution mapping of the MCF10 series of cell lines to identify specific gene targets to elucidate the molecular correlates of immortalization, development, and progression of breast cancer at the level of individual genes. DESIGN: We evaluated the initial untransformed outgrowths (MCF-10MS and MCF-10A) with six transformed cell lines with benign proliferations (MCF-10AT1, MCF-10AT1kcl2), carcinoma in situ (MCF-10CA1h cl13), and invasive carcinoma (MCF-10CA1h cl2, MCF-10CA1a cl1, MCF-10CA1d cl1). Losses and gains of loci at 112 unique human genome sites were interrogated using the multiplex ligation-dependent probe amplification assay (MLPA). RESULTS: Cytogenetic alterations in the four benign progenitors that persisted in the CIS and invasive cell lines corresponded to gains and losses of genes by MLPA. MCF-10MS had only normal gene copies. The untransformed MCF-10A had cytogenetic gain of 5q13-qter with corresponding gains of the IL3, IL4 and IL12B genes at 5q31-q33; gain of distal 19q12-qter was reflected in gains in KLK3 and BAX gene loci at 19q13-q13.4. The observed genic gain of cMYC at 8q24.12 was not indicated by cytogenetics. The apparently balanced t(3;9) component of the t(3;9)(p13;p22)t(3;5)(p26;q31) resulted in complete loss of the CDKN2A and CDKN2B genes at 9p21. Additional clonal cytogenetic changes in the DCIS cell line (MCF-10A1h cl13) involving chromosomes 1, 3 and 10 persisted in the invasive progeny, with gain of corresponding genes at 1p13 (BCAR2, BCAR3, NRAS, TGFB2), at 3p12-13 (IL12A), and 3q21-27 (MME, PIK3CA, BCL6). CONCLUSIONS: Our study adopted a comprehensive exploration of genetic changes using high resolution molecular probes applied to the MCF10 family of cell lines to identify individual genes in a continuum starting from normal breast epithelial cells and progressing through immortalization, transformation and invasive malignancy. Homozygous loss of CDKN2A and CDKN2B genes and gain of MYC were initiating immortalization events. Transformation and progression to malignancy event were marked by gains of IL13, VEGF, HRAS, TRAF2, and BCAS2, IL12A, and MME, respectively.

Adult↗
PubMed2006

Therapeutic targets in melanoma: map kinase pathway.

Recent progress in our understanding of the genetic alterations that occur in the pathogenesis of melanoma provides exciting opportunities for therapy. The most important signaling pathways in melanoma lie downstream of NRAS: the RAS-BRAF-MAPK pathway. A great deal of attention has been focused on the high mutation rate in the BRAF oncogene, which approaches 60%, because BRAF itself is an appealing drug substrate and because of the central contribution of BRAF function to melanoma development that the mutation rate signifies. Agents that specifically target BRAF, such as sorafenib, as well as new molecules that function both upstream and downstream of BRAF, are being actively investigated.

Drug Therapy, Combination↗
PubMed1995

A screen for RAS mutations in individuals at risk of secondary leukaemia due to occupational exposure to petrochemicals.

Occupational exposure to petrochemicals, in particular benzene, has been identified as a risk factor in the development of acute leukaemia. A cohort of exposed (n = 44) and non-exposed individuals (n = 19) from the same petrochemical installation were screened by polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH) for the presence of mutations in the H, K, and NRAS cellular proto-oncogenes. A KRAS mutation was detected in one individual from the exposed group who was haematologically normal at the time of sampling. The presence of this mutation was confirmed by nude mouse tumorigenicity assay and positively identified as a K13 Gly-Asp substitution by cloning and sequencing.

Adult↗
PubMed1993

Analysis of karyotype, SCE, and point mutation of RAS oncogene in Indian MDS patients.

Thirty Indian patients diagnosed as having primary myelodysplastic syndrome as per the French-American-British classification were investigated, on admission, for the frequencies of nonrandom karyotype abnormalities, sister chromatid exchange, and point mutations of the RAS oncogene. Successful karyotype analysis was possible in 24 patients, of whom 9 (37.5%) showed nonrandom karyotypic changes. Anomalies of chromosomes 5, 7, and 8 were detected in their bone marrow (BM). In addition, two new anomalies, del(8)(q22) and +19, were observed for the first time in our series. Six MDS patients were studied for SCE in either BM or peripheral blood. These data revealed a normal SCE incidence. Of the 10 MDS patients studied for point mutations of NRAS 12 and 61 and KRAS 12 and 61, one patient exhibited a base substitution at position 1 of the 12th codon of the KRAS gene. These data, gathered for the first time on the Indian patients, throw some light on the nature of genetic changes in MDS of our country.

Adolescent↗