1. ¹Department of Molecular Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA
2. ²Department of Anatomical Pathology, Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, Australia
3. ³Sydney Melanoma Unit, Sydney Cancer Center, Royal Prince Alfred Hospital, Camperdown, Australia
4. ⁴Division of Surgical Oncology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA

Correspondence: Dr DS Hoon, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd., Santa Monica, CA 90404, USA. E-mail: hoon@jwci.org

Received 23 November 2008; Revised 11 March 2009; Accepted 15 May 2009; Published online 29 June 2009.

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.