Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma

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...

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Autores principales: Narita, N, Tanemura, A, Murali, R, Scolyer, RA, Huang, S, Arigami, T, Yanagita, S, Chong, KK, Thompson, JF, Morton, DL, Hoon, DS
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738597/
https://www.ncbi.nlm.nih.gov/pubmed/19561646
http://dx.doi.org/10.1038/onc.2009.164
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author Narita, N
Tanemura, A
Murali, R
Scolyer, RA
Huang, S
Arigami, T
Yanagita, S
Chong, KK
Thompson, JF
Morton, DL
Hoon, DS
author_facet Narita, N
Tanemura, A
Murali, R
Scolyer, RA
Huang, S
Arigami, T
Yanagita, S
Chong, KK
Thompson, JF
Morton, DL
Hoon, DS
author_sort Narita, N
collection PubMed
description 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 are frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.
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spelling pubmed-27385972010-02-27 Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma Narita, N Tanemura, A Murali, R Scolyer, RA Huang, S Arigami, T Yanagita, S Chong, KK Thompson, JF Morton, DL Hoon, DS Oncogene Article 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 are frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression. 2009-06-29 2009-08-27 /pmc/articles/PMC2738597/ /pubmed/19561646 http://dx.doi.org/10.1038/onc.2009.164 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Narita, N
Tanemura, A
Murali, R
Scolyer, RA
Huang, S
Arigami, T
Yanagita, S
Chong, KK
Thompson, JF
Morton, DL
Hoon, DS
Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title_full Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title_fullStr Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title_full_unstemmed Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title_short Functional RET G691S Polymorphism in Cutaneous Malignant Melanoma
title_sort functional ret g691s polymorphism in cutaneous malignant melanoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2738597/
https://www.ncbi.nlm.nih.gov/pubmed/19561646
http://dx.doi.org/10.1038/onc.2009.164
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