Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2004 Feb;122(2):337-41.
doi: 10.1046/j.0022-202X.2004.22243.x.

Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma

Hensin Tsao  1 , Vikas Goel, Heng Wu, Guang Yang, Frank G Haluska
Affiliations

Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma

Hensin Tsao et al. J Invest Dermatol. 2004 Feb.

Abstract

Extant evidence implicates growth factor signaling in the pathogenesis of many tumor types, including cutaneous melanoma. Recently, reciprocal activating mutations of NRAS and BRAF were found in benign melanocytic nevi and cutaneous melanomas. We had previously reported a similar epistatic relationship between activating NRAS mutations and inactivating PTEN/MMAC1 alterations. We thus hypothesized that BRAF and PTEN/MMAC1 mutations may cooperate to promote melanoma tumorigenesis. Overall, 40 of 47 (85%) melanoma cell lines and 11 of 16 (69%) uncultured melanoma metastases had mutations in NRAS, BRAF, or PTEN/MMAC1. NRAS was exclusively mutated in nine of 47 (19%) cell lines and two of 16 (13%) metastases, whereas BRAF was solely mutated in 28 of 47 (60%) cell lines and nine of 16 (56%) metastases. In the 12 of 15 melanoma cell lines (80%) and two of two melanoma metastases with PTEN alterations, BRAF was also mutated. These findings suggest the existence of possible cooperation between BRAF activation and PTEN loss in melanoma development.

PubMed Disclaimer

Figures

Figure 1
Figure 1. (A) PCR–single strand conformation polymorphism
Analysis of BRAF exon 15. Amplified exon 15 fragments containing the normal (V599) and mutant (E599) variants exhibit differential mobilities, as indicated by the upper and lower arrows, respectively. The asterisk marks the presence of the mutant allele. Note that the cell line in lane 3 is homozygous for the E599 mutation (lane 1: Mel-Swift; lane 2: MGH-BO-1; lane 3: SK-Mel 28; lane 4: WM455; lane 5: SK-Mel 63). (B) BRAF genotypes showing loss of normal allele at codon 599.
Figure 2
Figure 2. Model of various genetic interactions
(A) Normal NRAS stimulates BRAF and PI3-K thereby activating downstream effectors MAPK and AKT, respectively. (B) An NRAS mutation activates both pathways. (C) Activation of BRAF accompanied by concurrent loss of PTEN cooperate to trigger signaling in both pathways. (D) An isolated BRAF mutation unaccompanied by PTEN loss may still engage the AKT signaling through unknown mechanisms.
See this image and copyright information in PMC

Comment in

  • Deletion of PTENP1 pseudogene in human melanoma.
    Poliseno L, Haimovic A, Christos PJ, Vega Y Saenz de Miera EC, Shapiro R, Pavlick A, Berman RS, Darvishian F, Osman I. Poliseno L, et al. J Invest Dermatol. 2011 Dec;131(12):2497-500. doi: 10.1038/jid.2011.232. Epub 2011 Aug 11. J Invest Dermatol. 2011. PMID: 21833010 Free PMC article. No abstract available.

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of Ras signaling. Oncogene. 1998;17:1395–1413. - PubMed
    1. Cohen C, Zavala-Pompa A, Sequeira JH, et al. Mitogen-activated protein kinase activation is an early event in melanoma progression. Clin Cancer Res. 2002;8:3728–3733. - PubMed
    1. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. - PubMed
    1. Dhawan P, Singh AB, Ellis DL, Richmond A. Constitutive activation of Akt/protein kinase B in melanoma leads to up-regulation of nuclear factor-kappaB and tumor progression. Cancer Res. 2002;62:7335–7342. - PubMed
    1. Diaz R, Ahn D, Lopez-Barcons L, et al. The N-ras proto-oncogene can suppress the malignant phenotype in the presence or absence of its oncogene. Cancer Res. 2002;62:4514–4518. - PubMed

Publication types

MeSH terms

-