Gene expression signature associated with BRAF mutations in human primary cutaneous melanomas.
With the aim to correlate BRAF mutation status with gene expression in human primary cutaneous melanomas, and thus to get more insight on the consequences of BRAF mutation on cell biology, we analyzed all expression data obtained in melanomas from which DNA was extracted from the same tissue slides that were used for the expression study. A cohort of 69 frozen primary melanoma whose oligonucleotide micro-array expression data were available, were genotyped for BRAF and NRAS genes. The expression data from these melanomas were re-analyzed according to BRAF mutational status. A set of 250 probes representing 209 genes that were significantly (raw P< or =0.001) associated with BRAF mutation status was identified and 17 of these were previously shown to be implicated in cutaneous melanoma progression or pigmentation pathway-associated genes driven by the microphthalmia transcription factor (MITF). The list of 34 top probes contained no more than 1% of false discoveries with a probability of 0.95. Among the genes that differentiated most strongly between BRAF mutated and non-mutated melanomas, there were those involved in melanoma immune response such as MAGE-D2, CD63, and HSP70. These findings support the immunogenicity of BRAF(V600E), eliciting patients T-cell responses in various in vitro assays. The genes whose expression is associated with BRAF mutations are not simply restricted to the MAPK/ERK signaling but also converge to enhanced immune responsiveness, cell motility and melanosomes processing involved in the adaptative UV response.
Kannengiesser
Caroline
C
Service de Génétique & CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France.
Spatz
Alain
A
Michiels
Stefan
S
Eychène
Alain
A
Dessen
Philippe
P
Lazar
Vladimir
V
Winnepenninckx
Véronique
V
Lesueur
Fabienne
F
Druillennec
Sabine
S
Robert
Caroline
C
van den Oord
Joost J
JJ
Sarasin
Alain
A
Bressac-de Paillerets
Brigitte
B
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002465:Cell Movement / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015342:DNA Probes / Q000592:standards; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007109:Immunity / Q000235:genetics; D007223:Infant; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D020460:Melanosomes; D008875:Middle Aged; D020125:Mutation, Missense; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays; D055815:Young Adult
D015342:DNA Probes; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf