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RNA-sequencing of Fes KO and WT melanomas

ABSTRACT: Publication abstract: An incomplete view of the (epi)genetic events that drive melanoma initiation and progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. Recent approaches that integrate human melanoma genomic and transcriptomic data provide unprecedented opportunities to discover oncogenic melanoma drivers. One limitation, however, is that human melanoma genome exhibits a radically altered cytogenetic profile. There is therefore the need for biologically-meaningful approaches to identify and validate lesions that drive melanomagenesis. We combined comparative oncogenomic approaches with mouse modeling to identify new cancer genes/pathways that drive melanoma progression. Spontaneously acquired genetic alterations such as copy-number alterations and specific mutations in mouse tumors of defined genetic origin were identified and used to prioritize relevant lesions from the complex human melanoma genomes. This integrated effort confirmed the importance of several genes and pathways previously implicated in melanoma and identified new putative melanoma tumor suppressor genes. Genetic ablation of one such gene, c-Fes, cooperated with BRafv600E to accelerate melanomagenesis in mice. This comparative oncogenomic approach has therefore helped discover a series of novel melanoma tumor suppressor genes, including c-FES, with prognostic and therapeutic relevance in human melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE83580 | GEO | 2017/06/21

SECONDARY ACCESSION(S): PRJNA326413

REPOSITORIES: GEO

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Project description:The identification of novel tumor-specific markers may improve understanding of melanoma progression and prognostic accuracy. Whole genome expression profiling of 46 primary melanomas, 12 metastases, and 16 normal skin samples using Affymetrix U133 PLUS 2.0 array generated gene lists including both known and new melanoma genes. The molecular genetic alterations contributing to the pathogenesis of melanoma are incompletely defined and few independent prognostic features have been identified beyond the pathologic characteristics of the primary tumor. Early stage melanoma is frequently curable, in contrast to the inferior prognosis of melanomas with regional lymph nodes involvement and the incurability of distant metastatic disease. The identification of novel tumor-specific markers may improve our understanding of melanoma progression and prognostic accuracy. To find differentially expressed genes that can distinguish melanoma from normal tissue, we performed a whole genome expression profiling of 46 primary melanoma samples, 12 regional or distant metastases, and 16 normal skin samples using Affymetrix U133 2.0 Plus array. Our study generated lists of differentially expressed genes in melanoma and identified novel prognostic marker HMGA2. It is a novel, highly overexpressed melanoma gene associated with poor prognosis. The overexpression of HMGA2 is strongly associated with regional and distant metastases and serves as an independent predictor of disease-free survival and overall survival in melanoma. Melanoma samples were obtained through an IRB-approved protocol using informed consent at the University of Michigan Multidisciplinary Melanoma Clinic. A portion of pigmented lesions clinically suspicious for melanoma and known melanoma were sampled by punch biopsy at the time of excision. The punch biopsy was bisected; half was sent to for clinical diagnosis and the other half along with adjacent normal skin when available immediately snap-frozen in liquid nitrogen. Snap-frozen tissue was embedded in OCT (TissueTek) followed by frozen sectioning and H&E slide preparation. The slides were evaluated by dermatopathologist who identified areas with greater than 70% tumor cellularity, which were sampled for RNA extraction. Primary melanomas and melanoma metastases were derived from different patients. Metastatic samples included lymph nodes (n=8), subcutaneous soft tissue (n=2), spleen (n=1), and small intestine (n=1).

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RNA-sequencing of Fes KO and WT melanomas

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