Thin and thick primary cutaneous melanomas reveal distinct patterns of somatic copy number alterations.
Cutaneous melanoma is one of the most aggressive type of skin tumor. Early stage melanoma can be often cured by surgery; therefore current management guidelines dictate a different approach for thin (<1mm) versus thick (>4mm) melanomas. We have carried out whole-exome sequencing in 5 thin and 5 thick fresh-frozen primary cutaneous melanomas. Unsupervised hierarchical clustering analysis of somatic copy number alterations (SCNAs) identified two groups corresponding to thin and thick melanomas. The most striking difference between them was the much greater abundance of SCNAs in thick melanomas, whereas mutation frequency did not significantly change between the two groups. We found novel mutations and focal SCNAs in genes that are embryonic regulators of axon guidance, predominantly in thick melanomas. Analysis of publicly available microarray datasets provided further support for a potential role of Ephrin receptors in melanoma progression. In addition, we have identified a set of SCNAs, including amplification of BRAF and ofthe epigenetic modifier EZH2, that are specific for the group of thick melanomas that developed metastasis during the follow-up. Our data suggest that mutations occur early during melanoma development, whereas SCNAs might be involved in melanoma progression.
Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy.
Valentina
V
Montagnani
Diagnostic Genetics Unit, Careggi University Hospital, Florence, Italy.|Center for Integrative Biology, University of Trento, Trento, Italy.
Matteo
M
Benelli
Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy.
Alessandro
A
Apollo
Diagnostic Genetics Unit, Careggi University Hospital, Florence, Italy.
Chiara
C
Pescucci
CBM - Genomics, Area Science Park, Basovizza, Trieste, Italy.
Danilo
D
Licastro
Anatomic Pathology Unit, Dermatopathology Section, S.M. Annunziata Hospital, Florence, Italy.
Carmelo
C
Urso
Plastic Surgery Unit, S.M. Annunziata Hospital, Regional Melanoma Referral Center, Istituto Toscano Tumori, Florence, Italy.
Gianni
G
Gerlini
Plastic Surgery Unit, S.M. Annunziata Hospital, Regional Melanoma Referral Center, Istituto Toscano Tumori, Florence, Italy.
Lorenzo
L
Borgognoni
Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy.
Lucio
L
Luzzatto
Core Research Laboratory, Istituto Toscano Tumori, Florence, Italy.|Department of Oncology, Careggi University Hospital, Florence, Italy.
Barbara
B
Stecca
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D036081:Receptors, Eph Family / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D036081:Receptors, Eph Family; D048493:Proto-Oncogene Proteins B-raf
exome sequencing; melanoma; somatic copy number alterations