N-ras Mutations are Common in Melanomas from Sun-Exposed Skin of Humans but Rare in Mucosal Membranes or Unexposed Skin

Jiveskog, S; Ragnarsson-Olding, Boel; Platz, Anton; Ringborg, Ulrik

doi:10.1046/j.1523-1747.1998.00376.x

Cited by 138 publications

(103 citation statements)

References 17 publications

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“…17 Mutations in members of the ras family genes, especially N-ras, are often found in cutaneous conditions, such as cutaneous melanoma, associated with exposure to UVR. 10,11 However, it has been reported that N-ras mutations are considerably more rare in mucosal lesions than in cutaneous lesions. 10 In a previous study assessing the role of N-ras mutations in conjunctival melanomas, no such mutations were detected.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Mutations in genes of the ras family, including Harvey-Ras (H-ras), Kirsten-Ras (Ki-ras), and Neuroblastoma-ras (N-ras), have been detected in cultured cells of mouse skin tumours following exposure to near-UVR 9 and are also frequently detected in human neoplastic conditions of sun-exposed body areas, such as cutaneous melanomas. 10 Such mutations may convert these genes into active oncogenes. 11 Therefore, it is reasonable to assume that mutations in these genes may also be present in ophthalmic pterygia.…”

Section: Introductionmentioning

confidence: 99%

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Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

Detorakis

Zafiropoulos

Arvanitis

et al. 2004

Eye

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Aims Ophthalmic pterygium is a potentially vision-threatening lesion of unknown etiology, related to an exposure to solar light. Mutations to the ras genes are frequently observed in lesions related to an exposure to solar light. The present study aims at screening pterygia for mutations at codons 12 and 13 of the ras genes. Methods In all, 50 pterygia were examined, together with respective blood samples and specimens of normal conjunctiva. A PCR reaction was performed to amplify sequences containing codons 12 and 13 of Ki-ras, H-ras, and N-ras. An RFLP analysis was then performed to detect point mutations at codon 12. The mutational status at codons 12 and 13 was further explored with sequencing of PCR products.Results RFLP analysis revealed Ki-ras mutations at codon 12 in five (10%) of pterygia, whereas H-ras or N-ras mutations were not observed. Sequencing confirmed Ki-ras mutations at codon 12 and revealed absence of mutations at codon 13. The presence of Ki-ras mutations was significantly correlated with postoperative recurrence (P ¼ 0.02) and young age (P ¼ 0.04). Mutations were not observed in specimens of blood or normal conjunctiva for any of the genes examined. Conclusions The absence of N-ras mutations is in agreement with previous reports concerning mucosal lesions. The detection of Ki-ras mutations and the association with postoperative recurrence implies a possible role of Ki-ras in the clinical profile of pterygium. The mechanism of Ki-ras mutations is unclear and could be independent of the action of UV light.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

Detorakis

Zafiropoulos

Arvanitis

et al. 2004

Eye

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“…h This P-value represents the overall statistically significant difference in the level of frequency of allelic losses between cases with and without BRAF/N-ras mutation. Bold type indicates LOH Mutations in the human N-ras gene have been reported mainly in melanomas on the sun-exposed sites (Jiveskog et al, 1998). The most common sequence alteration in the BRAF gene, in melanomas, is not a typical UV-associated mutation.…”

Section: Discussionmentioning

confidence: 99%

Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9

Kumar

Angelini

Hemminki³

2003

Oncogene

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We searched and report mutations in the BRAF and N-ras genes in 22 out of 35 (63 percent) primary sporadic melanomas. In three melanomas, mutations were concomitantly present in both genes. In all, 10 out of 12 mutations in the BRAF gene involved the 'hot spot' codon 600 (In all communications on mutations in the BRAF gene, the nucleotide and codon numbers have been based on the NCBI gene bank nucleotide sequence NM_004333. However, according to NCBI gene bank sequence with accession number NT_007914, there is a discrepancy of one codon (three nucleotides) in exon 1 in the sequence with accession number NM_004333. The sequence analysis of exon 1 of the BRAF gene in our laboratory has shown that the sequence derived from NT_007914 is correct (Kumar et al., 2003). Due to the correctness of the latter, sequence numbering of codons and nucleotides after exon 1 are changed by þ 1 and þ 3, respectively.), one tandem CT1789-90TC base change represented a novel mutation and another mutation caused a G466R aminoacid change within the glycine-rich loop in the kinase domain. Mutations in the N-ras gene in 11 melanomas were at codon 61 whereas two melanomas carried mutations in codon 12 including a tandem mutation GG4AA. We observed an inverse association between BRAF/N-ras mutations and the frequency of loss of heterozygosity (LOH) on chromosome 9 at 10 different loci. Melanomas with BRAF/N-ras mutations showed a statistically significant decreased frequency of LOH on chromosome 9 compared with cases without mutations (mean fractional allelic loss (FAL) ¼ 0.2970.23 vs 0.7270.33; t-test, P ¼ 0.0001). Difference in the FAL value between tumours with and without BRAF/N-ras mutations on 33 loci on five other chromosomes was not statistically significant (mean FAL 0.1770(mean FAL 0. .19 vs 0.2570 t-test, P ¼ 0.24). Melanoma cases with BRAF/N-ras mutations were also associated with lower age at diagnosis than cases without mutations (mean age 80.3877.24 vs 65.77719.79 years; t-test, P ¼ 0.02). Our data suggest that the occurrence of BRAF/N-ras mutations compensate the requirement for the allelic loss at chromosome 9, which is one of the key events in melanoma.

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“…6,7,10,11 In sporadic melanoma cases, the frequency of NRAS alterations reported varies in different studies. [12][13][14] In a study performed by our group, 28% of primary melanomas and 37% of metastatic tumors were found to harbor NRAS codon 61 mutations. 11 In contrast to sporadic melanoma cases, we have recently demonstrated a very high frequency (95%) of activating codon 61 NRAS mutations in the tumor cells of hereditary melanomas from individuals carrying CDKN2A germ line mutations.…”

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confidence: 99%

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

Eskandarpour¹,

Kiaii²,

Zhu³

et al. 2005

Intl Journal of Cancer

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The majority of human melanomas harbor activating mutations in either the BRAF or NRAS gene. To date, the role of oncogenic NRAS in melanoma remains poorly defined and no current therapies are directed at specifically suppressing oncogenic NRAS in human melanoma tumors. The aim of our study, therefore, was to investigate the effects of suppressing oncogenic NRAS in human melanoma cell lines in vitro. Using both small interfering RNAand plasmid based-RNA interference techniques, oncogenic NRAS was specifically suppressed in 2 human melanoma cell lines, 224 and BL, which harbor a codon 61 CAA (glutamine) to CGA (arginine) NRAS mutation. Suppression of oncogenic NRAS in these cell lines resulted in increased apoptosis. Furthermore, in 224 cells we demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and reduced expression of NF-kB and cyclin D1 in the N-Ras signaling pathway. In contrast, RNA interference directed at wild-type (WT) NRAS had no significant effect on apoptosis of 224 cells or 2 human melanoma cell lines (A375 and 397) containing WT NRAS but a codon 600 GTG (valine) to GAG (glutamate) mutation in BRAF. These data suggest that oncogenic NRAS is important for avoidance of apoptosis in melanomas that harbor the codon 61 NRAS mutation and emphasizes oncogenic NRAS as a therapeutic target in patients with tumors that harbor this mutation. ' 2005 Wiley-Liss, Inc.Key words: RNAi; melanoma; Ras; signal transduction; apoptosis Activation of Ras is a common molecular event in the etiology of human cancer. 1 The Ras proteins H-, K-and N-Ras are central regulators of cellular signal transduction processes leading to cell growth and differentiation. In the resting cell, Ras proteins are in the guanosine diphosphate (GDP)-bound inactive state. However, in response to receptor protein tyrosine kinases or other growth factor-dependent stimuli, these Ras proteins become activated by binding guanosine triphosphate (GTP). 2,3 Oncogenic mutations in codons 12, 13 and 61 of RAS genes prevent GTP hydrolysis, resulting in constitutively active Ras proteins. Such mutations that change the protooncogene RAS to an active oncogene are found in approximately 30 to 50% of human tumors. [4][5][6][7][8] Ras has also been demonstrated to be important for both the genesis and maintenance of melanoma. For instance, in a doxycycline-inducible H-Ras V12G mouse melanoma model, withdrawal of doxycycline was demonstrated to result in histological regression of primary and implanted tumors accompanied by marked apoptosis of melanoma cells. 9 Studies on melanoma tumors have confirmed that oncogenic activation of NRAS constitutes the predominant RAS alteration in cutaneous melanoma, with NRAS codon 61 mutations being the most common alterations and codon 12 and 13 mutations being less frequent. 6,7,10,11 In sporadic melanoma cases, the frequency of NRAS alterations reported varies in different studies. [12][13][14] In a study performed by our group, 28% of primary melanomas and 37% of metastatic tumo...

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N-ras Mutations are Common in Melanomas from Sun-Exposed Skin of Humans but Rare in Mucosal Membranes or Unexposed Skin

Cited by 138 publications

References 17 publications

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

Detection of point mutations at codon 12 of KI-ras in ophthalmic pterygia

Activating BRAF and N-Ras mutations in sporadic primary melanomas: an inverse association with allelic loss on chromosome 9

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

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