Genomic profiling of malignant melanoma using tiling-resolution arrayCGH.
Malignant melanoma is an aggressive, heterogeneous disease where new biomarkers for diagnosis and clinical outcome are needed. We searched for chromosomal aberrations that characterize its pathogenesis using 47 different melanoma cell lines and tiling-resolution bacterial artificial chromosome-arrays for comparative genomic hybridization. Major melanoma genes, including BRAF, NRAS, CDKN2A, TP53, CTNNB1, CDK4 and PTEN, were examined for mutations. Distinct copy number alterations were detected, including loss or gain of whole chromosomes but also minute amplifications and homozygous deletions. Most common overlapping regions with losses were mapped to 9p24.3-q13, 10 and 11q14.1-qter, whereas copy number gains were most frequent on chromosomes 1q, 7, 17q and 20q. Amplifications were delineated to oncogenes such as MITF (3p14), CCND1 (11q13), MDM2 (12q15), CCNE1 (19q12) and NOTCH2 (1p12). Frequent findings of homozygous deletions on 9p21 and 10q23 confirmed the importance of CDKN2A and PTEN. Pair-wise comparisons revealed distinct sets of alterations, for example, mutually exclusive mutations in BRAF and NRAS, mutual mutations in BRAF and PTEN, concomitant chromosome 7 gain and 10 loss and concomitant chromosome 15q22.2-q26.3 gain and 20 gain. Moreover, alterations of the various melanoma genes were associated with distinct chromosomal imbalances suggestive of specific genomic programs in melanoma development.
Jönsson
G
G
Department of Oncology, University Hospital, Lund, Sweden.
Dahl
C
C
Staaf
J
J
Sandberg
T
T
Bendahl
P-O
PO
Ringnér
M
M
Guldberg
P
P
Borg
A
A
D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D005784:Gene Amplification; D018628:Gene Dosage; D052138:Genes, Neoplasm / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012878:Skin Neoplasms / Q000235:genetics*