Melanoma: What do all the mutations mean?

Davis, Elizabeth J.; Johnson, Douglas B.; Sosman, Jeffrey A.; Chandra, Sunandana

doi:10.1002/cncr.31345

Cited by 140 publications

(142 citation statements)

References 100 publications

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“…Although no statistically significant association between BRD9 expression and tumour stage or survival was found in our study, BRD9 importance must not be overlooked, since the available literature states that expression alterations in other important genes such as CDKN2A also do not correlate with patient prognosis in melanoma [35][36][37]44]; this could be the case of BRD9. Moreover, BRD9 inhibition has been shown to result in decreased cell proliferation, G1-arrest, and apoptosis in rhabdoid tumour cell lines [45] and synovial sarcoma [41].…”

Section: Discussioncontrasting

confidence: 76%

“…Throughout our study, neither mutations on CDH23, ARHGEF40, and BRD9 nor expression of ARHGEF40 and BRD9 affected the overall survival of the patients. However, the literature indicates that CDKN2A, one of the most important genes for melanoma susceptibility, also does not correlate with patient survival, despite its important association with melanoma susceptibility [35][36][37]. Hence, the three variants identified in the present study may play an important role in melanoma susceptibility.…”

Section: Discussionmentioning

confidence: 50%

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High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Campos¹,

Fragoso²,

Luís³

et al. 2020

Genes

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Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.

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Section: Discussioncontrasting

confidence: 76%

Section: Discussionmentioning

confidence: 50%

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

Campos¹,

Fragoso²,

Luís³

et al. 2020

Genes

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“…Moreover, brain metastasis generally relates to intrinsic drug resistance properties (3). Investigating genetic traits of such tumor cells revealed a significant genetic diversity among melanoma tumors associated with high mutation rates, eventually accounting for the present difficulties in understanding the underlying mechanisms of metastasis (4). To draw general statements on the molecular events sustaining the development of metastasis proves to be a very challenging task, sometimes associated with apparently contradicting conclusions.…”

Section: Graphical Abstractmentioning

confidence: 99%

The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

Neuditschko

Janker²,

Niederstaetter³

et al. 2020

Molecular & Cellular Proteomics

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The prediction of metastatic properties from molecular analyses still poses a major challenge. Here we aimed at the classification of metastasis-related cell properties by proteome profiling making use of cutaneous and brain-metastasizing variants from single melanomas sharing the same genetic ancestry. Previous experiments demonstrated that cultured cells derived from these xenografted variants maintain a stable phenotype associated with a differential metastatic behavior: The brain metastasizing variants produce more spontaneous micro-metastases than the corresponding cutaneous variants. Four corresponding pairs of cutaneous and metastatic cells were obtained from four individual patients, resulting in eight cell-lines presently investigated. Label free proteome profiling revealed significant differences between corresponding pairs of cutaneous and cerebellar metastases from the same patient. Indeed, each brain metastasizing variant expressed several apparently metastasis-associated proteomic alterations as compared with the corresponding cutaneous variant. Among the differentially expressed proteins we identified cell adhesion molecules, immune regulators, epithelial to mesenchymal transition markers, stem cell markers, redox regulators and cytokines. Similar results were observed regarding eicosanoids, considered relevant for metastasis, such as PGE2 and 12-HETE. Multiparametric morphological analysis of cells also revealed no characteristic alterations associated with the cutaneous and brain metastasis variants. However, no correct classification regarding metastatic potential was yet possible with the present data. We thus concluded that molecular profiling is able to classify cells according to known functional categories but is not yet able to predict relevant cell properties emerging from networks consisting of many interconnected molecules. The presently observed broad diversity of molecular patterns, irrespective of restricting to one tumor type and two main classes of metastasis, highlights the important need to develop meta-analysis strategies to predict cell properties from molecular profiling data. Such base knowledge will greatly support future individualized precision medicine approaches.

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“…Diversity of phenotypes of distinct melanoma cell lines cultured in vitro in the same growth conditions can be explained by genotypic variations. Among human cancers, melanoma has one of the highest prevalences of mutations with a median of more than 10 mutations per megabase that usually carry ultraviolet light signature . Standard classification of melanoma bases mainly on clinical and histopathological criteria .…”

Section: Introductionmentioning

confidence: 99%

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

Hartman

Sztiller-Sikorska

Czyż

2019

Molecular Carcinogenesis

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We have extensively studied the phenotypic heterogeneity of patient-derived melanoma cells. Here, whole-exome sequencing revealed novel variants of genes associated with the MAPK, NOTCH, Hippo, cell-cycle, senescence, and ubiquitindependent pathways, which could contribute to the observed phenotypic diversity between cell lines. Focusing on mutations in the MAPK pathway-associated genes, we found BRAF (BRAF V600E ) and RAS subtypes, including NRAS Q61R and the rare HRAS Q61R variant, and additional alterations potentially leading to different ERK1/2 activity. Both RAS Q61R cell lines harbored a MEK1 P124S variant and exerted a low level of phospho-MEK1/2. Activity of the MAPK pathway was further attenuated in NRAS Q61R /MEK P124S cells by trametinib, and this effect was also shown in HRAS Q61R / MEK P124S melanoma cells. The observed variability in doubling time might be a consequence of diverse MAPK and PI3K/AKT pathway activities, but not exclusively, as a senescence program was also executed to different extent in distinct melanoma cell lines. Low percentages of senescent cells might result from mutations in CDKN2A, E2F3, and EZH2, and a high c-MYC expression. Vemurafenib and trametinib induced senescence concomitantly with c-MYC downregulation and irrespectively of CDKN2A mutation, but the EZH2 S412C variant might limit senescence induction. Damaging alterations in Hippo pathway-associated genes were accompanied with variability in the phosphorylation level of YAP1/TAZ and CTGF expression. Our study also suggests opposite activity of NOTCH2 F1209V and NOTCH2 N2002S variants. Additionally, we found a novel FBXW7 V418M variant that retained its function in melanoma cells. The obtained molecular data might be further exploited in genotype-phenotype relationship studies and in identifying novel biomarkers and therapies for melanomas.

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Melanoma: What do all the mutations mean?

Cited by 140 publications

References 100 publications

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma

The Challenge of Classifying Metastatic Cell Properties by Molecular Profiling Exemplified with Cutaneous Melanoma Cells and Their Cerebral Metastasis from Patient Derived Mouse Xenografts

Whole‐exome sequencing reveals novel genetic variants associated with diverse phenotypes of melanoma cells

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