Genotypic and gene expression studies in congenital melanocytic nevi: insight into initial steps of melanotumorigenesis.
Large congenital melanocytic nevi (CMNs) are said to have a higher propensity to malignant transformation compared with acquired nevi. Thus, they represent a good model for studying initial steps of melanotumorigenesis. We have performed genotypic (karyotype, fluorescence in situ hybridization, and mutational analyses) and differential expression studies on a large cohort of medium (n=3) and large (n=24) CMN. Chromosomal abnormalities were rare and single, a feature probably reflecting the benignity of these lesions. Mutational screening showed a high frequency of NRAS mutations in our series (19/27 cases, 70%), whereas BRAF mutations were less common (4/27 cases, 15%). Differential did not show significant alterations of cellular processes such as cell proliferation, cell migration/invasion, angiogenesis, apoptosis, and immune/inflammatory responses. However, significant downregulation of genes involved in pigmentation and upregulation of genes playing a role in DNA protection were observed. Lastly, our microarrays displayed upregulation of genes mediating chemoresistance in cancer. As alteration of pigmentation mechanisms can trigger oxidative damage, increased expression of genes involved in maintenance of DNA integrity might reflect the ability of nevocytic cells to self-protect against cellular stress. Furthermore, the observed alterations linked to chemoresistance might partially account for the well-known inefficacy of chemotherapy in malignant melanoma.
Dessars
Barbara
B
Inter-Disciplinary Research in Human, Molecular Biology Institute (IRIBHM), Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. bdessars@ulb.ac.be
De Raeve
Linda E
LE
Morandini
Renato
R
Lefort
Anne
A
El Housni
Hakim
H
Ghanem
Ghanem E
GE
Van den Eynde
Benoît J
BJ
Ma
Wenbin
W
Roseeuw
Diane
D
Vassart
Gilbert
G
Libert
Frédérick
F
Heimann
Pierre
P
D002465:Cell Movement; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008544:Melanocytes / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D009508:Nevus, Pigmented / Q000151:congenital / Q000235:genetics* / Q000378:metabolism*