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Functional RET G691S polymorphism in cutaneous malignant melanoma

Oncogene volume 28, pages 3058–3068 (2009)Cite this article

Abstract

RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), and its polymorphism at G691S juxtamembrane region (RETp) is a germline polymorphism. Cutaneous melanomas, particularly the desmoplastic subtype, are highly neurotropic; thus we sought to determine the frequency of RETp in cutaneous melanoma and its functional responsiveness to GDNF. RETp was assessed in 71 non-desmoplastic cutaneous melanomas (non-DMs) and 70 desmoplastic melanomas (DMs). Melanoma cell lines with RETp, RET wild type (RETwt), BRAF V600E mutation (BRAFmt) or BRAF wild type (BRAFwt) were assessed for functional activity. RETp frequency was significantly higher in DMs (61%) than in non-DMs (31%, P<0.001). BRAFmt was detected in only 11% of DMs. GDNF stimulation significantly amplified cell proliferation, migration and invasion in RETp, but not in RETwt melanoma cells. GDNF stimulation of RETp cell lines enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt of the RET-RAS-RAF-ERK and RET-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. GDNF response of RETp cells in signal transduction and other functional studies were not affected by BRAFmt. The study demonstrates that RETp is frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.

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Acknowledgements

We thank Sandy L Nguyen and Linhda Nguyen for expert editorial assistance and Emily H Liang for technical assistance. This work was supported by the National Institutes of Health, National Cancer Institute (Project II P0 CA029605 and CA012582 grants to DH); Ruth and Martin H Weil Foundation (to DH); the Leslie and Susan Gonda Foundation (to DH) and the Melanoma Foundation of the University of Sydney, Australia (to JT, RS, RM).

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Authors and Affiliations

  1. Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA

    N Narita, A Tanemura, S Huang, T Arigami, S Yanagita, K K Chong & D S Hoon

  2. Department of Anatomical Pathology, Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, Australia

    R Murali & R A Scolyer

  3. Sydney Melanoma Unit, Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, Australia

    R Murali, R A Scolyer & J F Thompson

  4. Division of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA

    D L Morton

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  1. N Narita
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Correspondence to D S Hoon.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Narita, N., Tanemura, A., Murali, R. et al. Functional RET G691S polymorphism in cutaneous malignant melanoma. Oncogene 28, 3058–3068 (2009). https://doi.org/10.1038/onc.2009.164

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