N-RAS mutations and susceptibility to lymphokine-activated killer (LAK) cells in human melanoma

Lupetti, Raffaella; Sensi, Marialuisa; Mortarini, Roberta; Anichini, Andrea; Clemente, C; Parmiani, Giorgio

doi:10.1097/00008390-199402000-00003

Cited by 10 publications

(6 citation statements)

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“…The results obtained with both mutational analysis were concordant and indicated that five of the clones (2/4, 2/14, 2/17, 2/51, 2/60) displayed the activating Q61R mutation at one of the alleles, whereas all remaining clones had wild-type NRAS alleles, in agreement with a previous report (Lupetti et al, 1994) (Table 1 and Figure 3, for representative results). Strikingly, the BRAF V600E mutation was detected in all clones with wild-type NRAS, whereas clones with mutated NRAS were wild-type for BRAF (Table1 and Figure 3, for representative results).…”

Section: Nrassupporting

confidence: 90%

“…Identification, by MASA-PCR, of a melanoma with concomitant NRAS and BRAF activating mutations Fourteen short-term melanoma cell lines harbouring activating exon 3 NRAS Q61R (7/14 lines) or exon 15 (7/14 tumours) BRAF V600E mutations, as detected by sequence analysis or oligonucleotide hybridization, were chosen for this study (Lupetti et al, 1994;Daniotti et al, 2004). All these melanoma lines were heterozygous for the mutated NRAS or BRAF genes and retained the corresponding wild-type allele.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical and pathological information of melanoma specimens as well as mutational status regarding RAS genes and BRAF exons 11 and 15 of the corresponding short-term cell lines has been previously described (Lupetti et al, 1994;Daniotti et al, 2004). Metastatic 665/1, 665/2, 665/R melanomas and primary 5810 melanoma led to the derivation of previously reported clonal cell lines (Anichini et al, 1989).…”

Section: Melanoma Cell Linesmentioning

confidence: 99%

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Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma

et al. 2006

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Activating BRAF or NRAS mutations have been found in 80% of human sporadic melanomas, but only one of these genetic alterations could be detected in each tumour. This suggests that BRAF and NRAS 'double mutants' may not provide advantage for tumour growth, or may even be selected against during tumorigenesis. However, by applying mutant-allele-specific-amplification-PCR method to short-term melanoma lines, one out of 14 tumours was found to harbour both BRAF V600E and the activating NRAS Q61R mutations. On the other hand, analysis of 21 melanoma clones isolated by growth in soft agar from this tumour indicated that 16/21 clones harboured a BRAF V600E, but were wild-type for NRAS, whereas the remaining had the opposite genotype (NRAS Q61R /wildtype BRAF). When compared to BRAF V600E clones, NRAS Q61R clones displayed reduced growth in soft agar, but higher proliferative ability in vitro in liquid medium and even in vivo after grafting into SCID/SCID mice. These data suggest that NRAS and BRAF activating mutations can coexist in the same melanoma, but are mutually exclusive at the single-cell level. Moreover, the presence of NRAS Q61R or BRAF V600E is associated with distinct in vitro and in vivo growth properties of neoplastic cells.

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Section: Nrassupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Melanoma Cell Linesmentioning

confidence: 99%

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Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma

et al. 2006

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“…Activating mutations in the KRAS and HRAS genes were, in contrast, registered at very low frequencies (Shukla et al., 1989; Ball et al., 1994; van Elsas et al., 1996; Jafari et al., 1995; Jiveskog et al., 1998; Reifenberger et al., 2004). The KRAS mutations were in several cases accompanied by NRAS mutations (Ball et al., 1994; Lupetti et al., 1994). Both KRAS and HRAS are therefore considered as having a rather weak oncogenic effect in melanoma.…”

Section: Ras/raf Activation In Melanomamentioning

confidence: 99%

Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site

et al. 2007

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A majority of cutaneous melanomas show activating mutations in the NRAS or BRAF proto-oncogenes, components of the Ras-Raf-Mek-Erk signal transduction pathway. Consistent data demonstrate the early appearance, in a mutually exclusive manner, of these mutations. The purpose of this paper is to summarize the literature on NRAS and BRAF activating mutations in melanoma tumors with respect to available data on histogenetic classification as well as body site and presumed UV-exposure. Common alterations of the signal transducing network seem to represent molecular hallmarks of cutaneous melanomas and therefore should continue to strongly stimulate design and testing of targeted molecular interventions.

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“…Amplifications were carried out as previously described for BRAF gene exons 11 and 15 , NRAS, KRAS and HRAS exons 1-2 (Albino et al, 1989;Lupetti et al, 1994), TP53 gene exons 5-8 (Donghi et al, 1993) and for CDK4 exon 2 (Wolfel et al, 1995). For PTEN, the following primers were used to amplify the genomic region flanking the identified mutated sequences: PTENEX7S, 5 0 -ATCCTCAGTTTGTGGTCTGCC-3 0 ; PTENEX7AS, 5 0 -GCATCTTG TTCTGTTTGTGGAAG-3 0 ; PTENINTR1S, 5 0 -TCCTTAACTAAAGTACTCAG-3 0 ; PTENINTR2AS, 5 0 -GCATTCTTACCTTACTACAT-3 0 .…”

Section: Pcr Analysismentioning

confidence: 99%

BRAF alterations are associated with complex mutational profiles in malignant melanoma

et al. 2004

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To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their expression in melanoma lesions. Owing to the lack of sufficient material from fresh specimens, we employed short-term cell lines obtained from melanoma biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11 cutaneous and two visceral metastases from patients with sporadic (n ¼ 31), familial (n ¼ 4) and multiple melanoma (n ¼ 2) were analysed. The results revealed novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall, activating mutations of BRAF and loss of functional p16 and ARF were detected in the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41 and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss associated with mutated BRAF V599E was the most represented (n ¼ 15). In addition, TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN loss was found in association with CDKN2A or TP53 mutations in the absence of BRAF activation. The p16/ARFD þ BRAF/ RAS profile was significantly associated with a longer survival, while complex mutational profiles were detected in highly aggressive disease and poor survival. These data support the existence of several molecularly defined melanoma groups which likely reflect different clinical/ biological behaviour, thus suggesting that a more extensive molecular classification of melanoma would significantly impact its clinical management.

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N-RAS mutations and susceptibility to lymphokine-activated killer (LAK) cells in human melanoma

Cited by 10 publications

References 0 publications

Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma

Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma

Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site

BRAF alterations are associated with complex mutational profiles in malignant melanoma

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