Chromosomal gains and losses in primary cutaneous melanomas detected by compartive genomic hybridization

Bastian, B.; LeBoit, P. E.; Hamm, Henning; Bröcker, E.-B.; Pinkel, Dan

doi:10.1016/s0923-1811(98)83846-2

Cited by 254 publications

(396 citation statements)

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“…The pattern of chromosomal aberrations included multiple gains and losses of whole chromosomes and chromosomal parts, as well as breaks within chromosomes suggesting structural rearrangements within the genome. The same pattern of chromosomal aberrations is well described as being character -1 3 5 8 11 15 7 10 12 14 13 19 21 22 Y X 18 17 16 istic of melanoma (especially melanoma arising on intermittently, non-chronic sun-exposed skin), 2,17 and was also observed in the control group of conventional superficial spreading melanoma. These observations support the existence of pronounced genomic instability in MLN, and provide biological evidence of their malignant nature.…”

Section: Discussionmentioning

confidence: 58%

“…1 Although histological evaluation is a reliable means of accurately classifying melanocytic tumors as benign (nevi) or malignant (melanoma), this distinction can be difficult in a minority of cases. Based on the fact that melanomas are characterized by chromosomal aberrations, molecular genetic tests such as comparative genomic hybridization (CGH) [2][3][4] and fluorescence in situ hybridization [5][6][7][8] have been shown to be useful ancillary techniques, which assist accurate classification of melanocytic tumors. Multiple chromosomal gains and losses are identified with CGH in the majority (495%) of melanomas, whereas melanocytic nevi typically lack chromosomal aberrations.…”

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confidence: 99%

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Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

et al. 2012

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Cutaneous melanomas are characterized by a range of histological appearances, and several morphological variants have been described. In this study, we report a variant of superficial spreading melanoma that is characterized by large, irregular junctional melanocytic nests. The junctional nests varied in shape and size, showed focal tendency to confluence, and were often surrounded by a cuff of epidermal keratinocytes. The melanocytes comprising the nests showed variable cytological atypia. In most of the cases, scant intraepidermal or junctional single melanocytes were seen, and other well-documented diagnostic criteria for melanoma were lacking, and as a result, histological recognition of these tumors as melanoma was difficult. Some cases were associated with an invasive dermal component or showed evidence of sun damage. To provide supporting evidence for malignancy, we analyzed these tumors for genomic aberrations. Using array comparative genomic hybridization (aCGH), we identified multiple genomic aberrations in all analyzed cases. A similar pattern of genomic aberrations was seen in a control group of bona fide superficial spreading melanomas, suggesting that these 'melanomas composed exclusively or predominantly of large nests' are indeed variants of superficial spreading melanoma. Fluorescence in-situ hybridization (FISH) was positive in 40% of the cases. However, using aCGH, the FISH-negative cases showed multiple genomic aberrations in regions that are not covered by FISH. The low sensitivity of the FISH test can be explained by the fact that FISH only evaluates four genomic loci for aberrations, whereas aCGH surveys the entire genome. In summary, we present histological and molecular genetic evidence for a morphological variant of superficial spreading melanoma. Awareness of the histological features will aid in their correct diagnosis as melanoma, and in difficult cases, judicious application of ancillary tests such as aCGH (rather than FISH) will assist accurate diagnosis. Modern Pathology (2012) 25, 838-845; doi:10.1038/modpathol.2012; published online 2 March 2012 Keywords: chromosomal aberrations; comparative genomic hybridization; fluorescence in-situ hybridization; melanocytic tumors; melanoma Cutaneous melanomas are characterized by a diverse range of histological appearances, and several morphological variants have been described. The most common subtypes in histological classification systems are superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. 1 Although histological evaluation is a reliable means of accurately classifying melanocytic tumors as benign

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Section: Discussionmentioning

confidence: 58%

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confidence: 99%

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

et al. 2012

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“…Genomic regions that exhibit losses of heterozygosity (LOH) and therefore suggest the presence of tumour suppressor genes in sporadic melanomas, have been identified, among others, at chromosomes 6q22-27 (Albino et al, 1994) and 11q22-23 (Robertson et al, 1999). Moreover, LOHs at chromosome 10 occur in 30 -60% of both early-and advanced-stage tumours (Newton, 1994;Bastian et al, 1998) and are an indicator of a poor clinical prognosis (Healy et al, 1998). Segmental deletions were cytogenetically localized to 10q (Richmond et al, 1986;Parmiter et al, 1988;Isshiki et al, 1993;Indsto et al, 1998) and subsequently narrowed by studies of LOH to 10q22-qter (Isshiki et al, 1993;Herbst et al, 1994;Walker et al, 1995;Healy et al, 1996).…”

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confidence: 99%

PTEN/MMAC1 expression in melanoma resection specimens

et al. 2002

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PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semiquantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/ MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.

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“…The role of UV exposure in inducing melanoma is still a matter of great controversy [46]. Recent molecular analysis of malignant melanoma [47] allows an alternative interpretation. A primary event in malignant melanoma appears to be loss of the region of chromosome 9p carrying the p16 familial melanoma gene that is part of the cell cycle checkpoint pathway [47].…”

Section: How Is Ner Integrated and Regulated In Cells And Tissues?mentioning

confidence: 99%

“…Recent molecular analysis of malignant melanoma [47] allows an alternative interpretation. A primary event in malignant melanoma appears to be loss of the region of chromosome 9p carrying the p16 familial melanoma gene that is part of the cell cycle checkpoint pathway [47]. Inspection of the chromosomal losses and gains reported in these melanomas indicate that subsequent to p16 losses, there are additional losses of 9q including the basal cell nevus and XPA genes, amplification of 6p carrying the pol gene (hRad30A), and loss of 6q containing the pol active subunit hRev3.…”

Section: How Is Ner Integrated and Regulated In Cells And Tissues?mentioning

confidence: 99%

Nucleotide excision repair “a legacy of creativity”

Cleaver

Karplus

Kashani‐Sabet

et al. 2001

Mutation Research/DNA Repair

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The first half of the 20th century has seen an enormous growth in our knowledge of DNA repair, in no small part due to the work of Dirk Bootsma, Philip Hanawalt and Bryn Bridges; those honored by this issue. For the new millennium, we have asked three general questions: (A) Do we know all possible strategies of nucleotide excision repair (NER) in all organisms? (B) How is NER integrated and regulated in cells and tissues? (C) Does DNA replication represent a new frontier in the roles of DNA repair? We make some suggestions for the kinds of answers the next generation may provide. The kingdom of archea represents an untapped field for investigation of DNA repair in organisms with extreme lifestyles. NER appears to involve a similar strategy to the other kingdoms of prokaryotes and eukaryotes, but subtle differences suggest that individual components of the system may differ. NER appears to be regulated by several major factors, especially p53 and Rb which interact with transcription coupled repair and global genomic repair, respectively. Examples can be found of major regulatory changes in repair in testicular tissue and melanoma cells. Our understanding of replication of damaged DNA has undergone a revolution in recent years, with the discovery of multiple low-fidelity DNA polymerases that facilitate replicative bypass. A secondary mechanism of replication in the absence of NER or of one or more of these polymerases involves sister chromatid exchange and recombination (hMre11/hRad50/Nbs1). The relative importance of bypass and recombination is determined by the action of p53. We hypothesise that these polymerases may be involved in resolution of complex DNA structures during completion of replication and sister chromatid resolution. With these fascinating problems to investigate, the field of DNA repair will surely not disappoint the next generation.

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Chromosomal gains and losses in primary cutaneous melanomas detected by compartive genomic hybridization

Cited by 254 publications

References 0 publications

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

Histological and genetic evidence for a variant of superficial spreading melanoma composed predominantly of large nests

PTEN/MMAC1 expression in melanoma resection specimens

Nucleotide excision repair “a legacy of creativity”

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