Somatic alterations in the melanoma genome: A high‐resolution array‐based comparative genomic hybridization study

Abstract

We performed DNA microarray-based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono-allelic and bi-allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1, CDK4, and other loci was significantly increased in cell lines without BRAF-NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued.

CEACAM1-3S Drives Melanoma Cells into NK Cell-Mediated Cytolysis and Enhances Patient Survival

“…33). Cell lines were established from malignant melanoma as described before (34,35). RPMI-1640 supplemented with 10% FCS, 1% penicillin/streptomycin, and 1% L-glutamine (all from PAA Laboratories) was used as culture medium.…”

Genomics of Human Malignant Melanoma

“…Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic opportunity to successfully treat this aggressive, chemoresistant disease. The discovery of new targets by array CGH was also reported by Gast et al [2010]. In this study, SNP arrays with 250,000 targets were applied to 60 cell lines derived from metastasised melanomas.…”

“…These data further confirm that distinct molecular pathways are involved in malignant melanomas, driving melanoma initiation and progression in association with either oncogenic BRAF or NRAS mutations complemented mainly by the loss of tumour suppressor genes, including CDKN2A and PTEN. Alternatively, they may implicate the amplification of CCDN1 (11q13) and CDK4, together with deletions of the 13q and 16q chromosome arms, which contain two major players, the RB1 and MC1R genes respectively [Gast et al, 2010]. Losses of the entire chromosome 13q region have been predominantly observed in melanoma cell lines without BRAF and NRAS oncogenic mutations.…”

Genomic Alterations in Pulmonary Adenocarcinoma In Situ in an Adolescent Patient

“…10 This list of genes was then compared to our list of amplified loci, corresponding to a total of 2580 genes. Among the most relevant genes identified (Table), ERBB2, ARNT, and NKX2-1 were described in a large-scale study of lung tumors by SNP array analysis.…”

“…8 Among the melanoma-related alterations, we identified KIT amplification, well described in acral melanoma. 10 …”