Genetic Interaction Between NRAS and BRAF Mutations and PTEN/MMAC1 Inactivation in Melanoma

Tsao, Hensin; Goel, Vikas; Wu, Heng; Guang, Yang; Haluska, Frank G.

doi:10.1046/j.0022-202x.2004.22243.x

Cited by 425 publications

(360 citation statements)

References 18 publications

Supporting

Mentioning

334

Contrasting

Unclassified

Order By: Relevance

“…In addition, we also confirmed that BRAF and NRAS mutations are mutually exclusive (Maldonado et al, 2003). However, our data also suggest that as there is no selection for coupled PTEN and NRAS mutations, both PTEN and BRAF mutation commonly occur in the same cells, emphasizing that BRAF is downstream of NRAS and does not affect the PI3K/PTEN pathway (Tsao et al, 2004). By searching for similar patterns of copy number changes, 11 concomitantly altered genomic pairs appeared ( Table 2).…”

Section: G Jönsson Et Alsupporting

confidence: 72%

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

et al. 2007

View full text Add to dashboard Cite

Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.

show abstract

Section: G Jönsson Et Alsupporting

confidence: 72%

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

et al. 2007

View full text Add to dashboard Cite

show abstract

“…3 Although linked to exposure to ultraviolet light, it is widely accepted that both genotypic and phenotypic changes in melanocytes predispose to melanocyte transformation and the onset of melanoma. 4,5 Surprisingly, p53 mutations are very rare in melanoma, but activity is, however, impaired through direct or indirect inactivation of key elements of this pathway, including through the suppression of APAF-1 expression, 6 loss of PTEN function, 7 dysregulation of Bcl-2 expression, 8 upregulation of the anti-apoptotic protein Mcl-1 together with its altered slice variant expression 9,10 and the ER chaperone GRP78. [11][12][13] Oncogenic mutations, however, in the Ras/Raf pathway are the most well-described genetic mutations associated with melanoma development and progression.…”

mentioning

confidence: 99%

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

et al. 2014

View full text Add to dashboard Cite

The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF V600E mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF V600E induces a chronic ER stress status directly increasing basal cell autophagy. BRAF V600E -mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF V600E -mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF V600E melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.

show abstract

“…26,30,32,34,[36][37][38][66][67][68][69][70][71] Only one atypical Spitz nevus from the arm of a 22-year-old female had an NRAS mutation in our study. As expected, this lesion lacked a BRAF mutation, since NRAS and BRAF mutations are mutually exclusive events.…”

Section: Discussionmentioning

confidence: 99%

“…Since then, many studies have reported BRAF mutations in benign and malignant melanocytic lesions. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] However, a number of studies have failed to demonstrate BRAF mutations in Spitz nevi. 25,[40][41][42][43][44][45][46][57][58][59][60][61] Most of these studies analyzed only classic Spitz nevi.…”

mentioning

confidence: 99%

BRAF and NRAS mutations in spitzoid melanocytic lesions

et al. 2006

View full text Add to dashboard Cite

BRAF mutations are common events in a variety of melanocytic nevi and primary cutaneous melanomas. We have previously found BRAF mutations in 82% of nevi, consisting of congenital, common acquired and dysplastic types, and 33% of primary cutaneous melanomas other than the spitzoid type, similar to other published reports. A small number of studies have evaluated Spitz nevi and have failed to detect any lesions possessing a BRAF mutation. Only one study included categories of atypical Spitz nevus and borderline lesions suspected to be spitzoid melanomas, along with classic Spitz nevi and spitzoid melanomas. We examined a spectrum of spitzoid lesions that included 48 Spitz nevi, some with atypical features, seven atypical (borderline) Spitz tumors, and 13 spitzoid melanomas. BRAF mutations were detected in 12 of 68 spitzoid lesions, of which two were spitzoid melanomas and 10 were Spitz nevi. Five of the 10 Spitz nevi with BRAF mutations were altered by more than usual cytologic atypia and/or architectural atypia overlapping with dysplastic nevi, or irritation/inflammation; one desmoplastic Spitz nevus had a BRAF mutation. These results indicate that a small subset of Spitz nevi, some with atypical histologic features, possess BRAF mutations. Therefore, the BRAF mutational status does not separate all Spitz nevi from spitzoid melanomas and non-Spitz types of melanocytic proliferations, contrary to previous reports.

show abstract

Genetic Interaction Between NRAS and BRAF Mutations and PTEN/MMAC1 Inactivation in Melanoma

Cited by 425 publications

References 18 publications

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

BRAF and NRAS mutations in spitzoid melanocytic lesions

Contact Info

Product

Resources

About