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Updated: Jun 22, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
GAB2 amplifications refine molecular classification of melanoma
Karen A Chernoff1, Lindsey Bordone, Basil Horst
1Departments of Dermatology and Pathology and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.
Purpose:
Gain-of-function mutations in BRAF, NRAS, or KIT are associated with distinct melanoma subtypes with KIT mutations and/or copy number changes frequently observed among melanomas arising from sun-protected sites, such as acral skin (palms, soles, and nail bed) and mucous membranes. GAB2 has recently been implicated in melanoma pathogenesis, and increased copy numbers are found in a subset of melanomas. We sought to determine the association of increased copy numbers of GAB2 among melanoma subtypes in the context of genetic alterations in BRAF, NRAS, and KIT.
Experimental Design:
A total of 85 melanomas arising from sun-protected (n = 23) and sun-exposed sites (n = 62) were analyzed for copy number changes using array-based comparative genomic hybridization and for gain-of-function mutations in BRAF, NRAS, and KIT.
Results:
GAB2 amplifications were found in 9% of the cases and were associated with melanomas arising from acral and mucosal sites (P = 0.005). Increased copy numbers of the KIT locus were observed in 6% of the cases. The overall mutation frequencies for BRAF and NRAS were 43.5% and 14%, respectively, and were mutually exclusive. Among the acral and mucosal melanomas studied, the genetic alteration frequency was 26% for GAB2, 13% for KIT, 30% for BRAF, and 4% for NRAS. Importantly, the majority of GAB2 amplifications occurred independent from genetic events in BRAF, NRAS, and KIT.
Conclusions:
GAB2 amplification is critical for melanomas arising from sun-protected sites. Genetic alterations in GAB2 will help refine the molecular classification of melanomas.
Insights
GAB2 amplification is crucial in melanomas of sun-protected sites, independent of BRAF, NRAS, and KIT mutations. This finding aids in refining melanoma molecular classification.
Area of Science:
- Oncology
- Genetics
- Dermatology
Background:
- Gain-of-function mutations in BRAF, NRAS, and KIT define distinct melanoma subtypes.
- KIT alterations are common in melanomas from sun-protected sites (acral, mucosal).
- GAB2 gene copy number increases are observed in a subset of melanomas.
Purpose of the Study:
- To investigate the association between GAB2 copy number and melanoma subtypes.
- To analyze GAB2 copy number in relation to BRAF, NRAS, and KIT genetic alterations.
- To understand the role of GAB2 in melanomas from sun-protected versus sun-exposed sites.
Main Methods:
- Analysis of 85 melanomas (23 sun-protected, 62 sun-exposed).
- Array-based comparative genomic hybridization for copy number changes.
- Detection of gain-of-function mutations in BRAF, NRAS, and KIT.
Main Results:
- GAB2 amplifications occurred in 9% of cases, significantly associated with acral and mucosal melanomas (P=0.005).
- KIT locus copy number increase observed in 6% of cases.
- BRAF (43.5%) and NRAS (14%) mutations were mutually exclusive. In acral/mucosal melanomas: GAB2 (26%), KIT (13%), BRAF (30%), NRAS (4%).
- Most GAB2 amplifications were independent of BRAF, NRAS, and KIT genetic events.
Conclusions:
- GAB2 amplification is a critical event in melanomas arising from sun-protected skin.
- Identifying GAB2 genetic alterations can refine the molecular classification of melanoma.
- GAB2 amplification represents a potential therapeutic target in specific melanoma subtypes.
