GAB2 amplifications refine molecular classification of melanoma.
OBJECTIVE
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.


METHODS
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.
Chernoff
Karen A
KA
Departments of Dermatology and Pathology and Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York, USA.
Bordone
Lindsey
L
Horst
Basil
B
Simon
Katherine
K
Twadell
William
W
Lee
Keagan
K
Cohen
Jason A
JA
Wang
Shuang
S
Silvers
David N
DN
Brunner
Georg
G
Celebi
Julide Tok
JT
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005784:Gene Amplification / Q000502:physiology; D018628:Gene Dosage; D005787:Gene Frequency; D011905:Genes, ras; D006801:Humans; D008297:Male; D008545:Melanoma / Q000145:classification* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012878:Skin Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects
D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf