Clinical correlates of NRAS and BRAF mutations in primary human melanoma.
OBJECTIVE
NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci.


METHODS
Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging.


RESULTS
Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups.


CONCLUSIONS
Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression.
Ellerhorst
Julie A
JA
Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. jaellerh@mdanderson.org
Greene
Victoria R
VR
Ekmekcioglu
Suhendan
S
Warneke
Carla L
CL
Johnson
Marcella M
MM
Cooke
Carolyn P
CP
Wang
Li-E
LE
Prieto
Victor G
VG
Gershenwald
Jeffrey E
JE
Wei
Qingyi
Q
Grimm
Elizabeth A
EA
D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D012883:Skin Ulcer
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf