Anatomic site-specific patterns of gene copy number gains in skin, mucosal, and uveal melanomas detected by fluorescence in situ hybridization

Glatz-Krieger, Katharina; Pache, Mona; Tapia, Coya; Fuchs, Alain H.; Savic, Spasenija; Glatz, Dieter; Mihatsch, Michael J.; Meyer, Peter

doi:10.1007/s00428-006-0167-8

Cited by 37 publications

(28 citation statements)

References 36 publications

(54 reference statements)

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“…The involvement of CDKN2A and C-MYC copy number changes in nodular type of melanoma has only been suggested so far (Cachia et al 2000;Treszl et al 2004;Glatz-Krieger et al 2006). The genes were analysed separately and limited information about their signiWcance, speciWcally in NM development, spread and prognosis has been reported.…”

Section: Introductionmentioning

confidence: 99%

Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma

Koynova

Jordanova

Kukutsch

et al. 2006

J Cancer Res Clin Oncol

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Section: Introductionmentioning

confidence: 99%

Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma

Koynova

Jordanova

Kukutsch

et al. 2006

J Cancer Res Clin Oncol

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“…used extensively, especially when sample size is limited, to evaluate individual chromosome imbalance, or copy number alteration (CNA) associated with metastatic progression (4), and to classify CNA related to anatomic site (5). Some of the genes identified include members of the receptor tyrosine kinase family (FGFR3, EGFR), oncogenes (KIT, MET, MYC), genes involved in development (MITF, WNT5A), and genes involved in regulation of cell cycle progression (CDKN2A) and apoptosis (APAF1).…”

mentioning

confidence: 99%

Detection of Copy Number Alterations in Metastatic Melanoma by a DNA FluorescenceIn situHybridization Probe Panel and Array Comparative Genomic Hybridization: A Southwest Oncology Group Study (S9431)

Moore

Persons

Sosman

et al. 2008

Clinical Cancer Research

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Purpose: Gene copy number alteration (CNA) is common in malignant melanoma and is associated with tumor development and progression. The concordance between molecular cytogenetic techniques used to determine CNA has not been evaluated on a large set of loci in malignant melanoma. Experimental Design: A panel of 16 locus-specific fluorescence in situ hybridization (FISH) probes located on eight chromosomes was used to identify CNA in touch preparations of frozen tissue samples from 19 patients with metastatic melanoma (SWOG-9431). A subset (n = 11) was analyzed using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH) of DNA isolated directly from touch-preparation slides. Results: By FISH, most samples showed loss near or at WISP3/6p21, CCND3/6q22, and CDKN2A/9p21 (>75% of samples tested). More than one third of CDKN2A/9p21 losses were biallelic. Gains of NEDD9/6p24, MET/7q31, and MYC/8q24 were common (57%, 47%, and 41%, respectively) and CNA events involving 9p21/7p12.3 and MET were frequently coincident, suggesting gain of the whole chromosome 7. Changes were confirmed by aCGH, which also uncovered many discreet regions of change, larger than a single BAC. Overlapping segments observed in >45% of samples included many of the loci analyzed in the FISH study, in addition to other WNT pathway members, and genes associated withTP53 pathways and DNA damage response, repair, and stability. Conclusions: This study outlines a set of CNAs at the gene and regional level, using FISH and aCGH, which may provide a benchmark for future studies and may be important in selection of individual therapy for patients with metastatic malignant melanoma.Skin cancer occurs in more than 1,200,000 Americans annually (1). Most cases are highly curable squamous and basal cell cancers, but f62,500 new cases of melanoma will be diagnosed this year in the United States. The incidence of melanoma has steadily been increasing, and melanoma causes more than 8,400 deaths per year in this country, accounting for the vast majority of skin cancer deaths (1). Early detection and surgery are key to improved survival. Once metastatic melanoma is diagnosed, median survival duration of only 6 to 9 months is expected.Primary melanoma lesions have largely been characterized by Breslow's depth, Clark's level, ulceration, microscopic involvement of regional lymph nodes, as well as mitotic index, lymphocyte infiltration, and signs of regression. Metastatic melanoma is staged based on location of lesions, such as skin, lymph nodes, lung, liver, and other organ sites, and finally, serum lactate dehydrogenase. With advances in genetic technology, new tools have been developed that may facilitate the collection of a set of potentially robust prognostic genetic indicators (2, 3) to augment the anatomic classifications.Cytogenetic, molecular, and biological studies indicate that multiple genetic alterations are involved in the development and progression of malignant melanoma, with several genes and chromosomal sites del...

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“…47 Alternatively, oncogenes amplified by copy number changes (eg, CCND1 and MYC1) were shown to exhibit site-specific frequencies in malignant melanoma. 48 Regarding clinical management the dichotomy between pure and mixed desmoplastic malignant melanoma further extends to prognosis as previously reported and limits therapy options in pure desmoplastic malignant melanoma. In conclusion, especially pure desmoplastic malignant melanoma appears to be the desmoplastic malignant melanoma subentity in need for further investigation regarding additional molecular driver mechanism and structural as well as numeric genome analysis to elucidate the oncogenic changes propagating tumor growth in this special melanoma subtype.…”

Section: Mutations In Desmoplastic Melanomamentioning

confidence: 93%

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

et al. 2015

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Desmoplastic malignant melanoma is a distinct melanoma entity histologically subtyped into mixed and pure forms due to significantly reduced lymph node metastases in the pure form. Recent reports investigating common actionable driver mutations have demonstrated a lack of BRAF, NRAS, and KIT mutation in pure desmoplastic melanoma. In search for alternative driver mutations next generation amplicon sequencing for hotspot mutations in 50 genes cardinal to tumorigenesis was performed and in addition the RET G691S polymorphism was investigated. Data from 21 desmoplastic melanomas (12 pure and 9 mixed) were retrieved. Pure desmoplastic melanomas were either devoid of mutations (50%) or displayed mutations in tumor suppressor genes (TP53, CDKN2A, and SMAD4) singularly or in combination with the exception of a PIK3CA double-mutation lacking established biological relevance. Mixed desmoplastic melanomas on the contrary were frequently mutated (89%), and 67% exhibited activating mutations similar to common-type cutaneous malignant melanomas (BRAF, NRAS, FGFR2, and ERBB2). Separate analysis of morphologically heterogeneous tumor areas in four mixed desmoplastic malignant melanomas displayed no difference in mutation status and RET G691 status. GNAQ and GNA11, two oncogenes in BRAF and NRAS wild-type uveal melanomas, were not mutated in our cohort. The RET G691S polymorphism was found in 25% of pure and 38% of mixed desmoplastic melanomas. Apart from RET G691S our findings demonstrate absence of activating driver mutations in pure desmoplastic melanoma beyond previously investigated oncogenes (BRAF, NRAS, and KIT). The findings underline the therapeutic dichotomy of mixed versus pure desmoplastic melanoma with regard to activating mutations primarily of the mitogen-activated protein kinase pathway.

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Anatomic site-specific patterns of gene copy number gains in skin, mucosal, and uveal melanomas detected by fluorescence in situ hybridization

Cited by 37 publications

References 36 publications

Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma

Increased C-MYC copy numbers on the background of CDKN2A loss is associated with improved survival in nodular melanoma

Detection of Copy Number Alterations in Metastatic Melanoma by a DNA FluorescenceIn situHybridization Probe Panel and Array Comparative Genomic Hybridization: A Southwest Oncology Group Study (S9431)

Mutational dichotomy in desmoplastic malignant melanoma corroborated by multigene panel analysis

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