Genotypic and Gene Expression Studies in Congenital Melanocytic Nevi: Insight into Initial Steps of Melanotumorigenesis

Abstract

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.

Nras in melanoma: Targeting the undruggable target

“…The frequency of NRAS mutations in medium-sized congenital nevi is 64-70% [39][40][41] and raises to 94.7% in large-giant congenital nevi where it has been recently recognized as the sole recurrent somatic mutation [42]. It has been suggested that NRAS mutations exert stronger growth signals, resulting in the formation of larger nevi than those linked to BRAF mutations [43].…”

Heterogeneity of Neoplastic Stem Cells: Theoretical, Functional, and Clinical Implications

“…Next generation DNA sequencing methods indicate that the cellular DNA repair machinery is unable to keep up with the background rate of errors that accumulate in the genomes of cells of multicellular organisms, most of which are likely to prove biologically inconsequential (4,(7)(8)(9)(10)(11)(12). In addition, there is growing evidence of changes in the molecular mechanisms that regulate stem cell differentiation and its control during normal development and aging, as well as in response to wounding, infections, and other perturbations of normal physiology (13)(14)(15)(16)(17)(18)(19).…”

Stabilization of C-RAF:KSR1 complex by DiRas3 reduces availability of C-RAF for dimerization with B-RAF

“…The expression of DiRas3 appeared strongly increased in endometriosis epithelial cells as compared to normal ovarian epithelial cells [49]. Furthermore, the expression of the DiRas3 gene was up-regulated in the keratinocytes from the large congenital melanocytic nevi bearing the activating B-RAF-V600E mutation [50]. 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 12 There is an increasing number of genes that originally have been assigned a tumour suppressor or an oncogenic role, but after further investigations appeared to have a dual function depending on cellular context.…”