Chromosomal imbalances in primary and metastatic melanomas: over-representation of essential telomerase genes.
Comparative genomic hybridization was used to map copy number abnormalities in 48 short-term cell cultures established from different stages and types of human melanoma. A variety of random and non-random chromosomal alterations were detected, with gains within chromosomes 20q, 7q, 7p, 20p, 6p and 17q and losses in 9p, 10q, 6q, 10p, 4q, and 11q being the most common observations. In addition, several other chromosomal loci were over- or under-represented in subgroups of melanomas. For example, sequences on 3q26 were over-represented in 33% and on 5p15.33 in 27% of cell cultures, reaching the level of amplification in 12% and 22%, respectively. These regions harbour the two essential genes for the enzyme telomerase: the telomerase reverse transcriptase gene (hTERT) on 5p15.33 and the telomerase RNA component gene (hTERC) on 3q26. Using fluorescence in situ hybridization and Southern blot analysis, both genes were shown to be over-represented or amplified in several melanomas. Interestingly, hTERT amplification was abundant in superficial spreading primary melanomas, subcutaneous metastases and malignant effusion-derived cells, but completely absent or very rare in primary nodular melanomas as well as brain, bone and lymph node metastases. Several chromosomes or chromosomal regions harbouring telomerase-suppressing activities (3p, 4, 6 and 10p) were frequently under-represented in melanomas. Our data suggest that genetic alterations at several chromosomal loci might facilitate activation of telomerase during the development of cutaneous malignant melanoma.
D000328:Adult; D000368:Aged; D015139:Blotting, Southern; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005260:Female; D018628:Gene Dosage; D006801:Humans; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D008677:Metaphase; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009693:Nucleic Acid Hybridization; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase