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Identification of drug resistance genes in melanoma

ABSTRACT: Our aim is to analyze the genome of human melanoma cell lines and short term culture from human melanoma samples in order to identify genes that confer drug resistance to clinically relevant targeted therapies. We will perform whole-exome sequencing, copy number variation analysis and methylome analysis in a collection of human melanoma cell lines and short term culture that will be then screened for drug sensitivity/resistance through a library of clinically relevant drugs and drug combinations. By the combined analysis of the genomic lesion and the drug sensitivity/resistance profile of different cell lines, we will look for genes whose mutation is associated to the sensitivity or resistance to a specific drug in different samples.

PROVIDER: EGAS00001000617 | EGA |

REPOSITORIES: EGA

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Project description:Melanoma recurrence frequently occurs after a latency period of several years. In vivo studies demonstrated that tumor cells overcoming latency show a T cell-edited phenotype, suggesting a relevant role for CD8+ T cells in maintaining metastatic latency. Here, in a patient model of multiple recurrent lesions, we illustrate the genetic evolution of poorly immunogenic melanoma phenotypes, evolving in the presence of autologous tumor antigen-specific CD8+ T cells. Melanoma cells from two of three late recurrent metastases, developing within a 6-year latency period, lacked HLA class I expression. HLA class I-negative tumor cells became clinically apparent 1.5 and 6 years into stage IV disease. Genome profiling by SNP arrays revealed total T-cell resistance in both metastases originating from a shared chromosome 15q alteration and independently acquired focal B2M gene deletions. A third HLA class I-positive lesion developed in year 3 of stage IV disease. By HLA haplotype loss lesion-derived melanoma cells acquired resistance towards dominant T-cell clonotypes targeting early stage III tumor cells. Early disease melanoma cells showed a dedifferentiated MITFnegative phenotype, recently described to be associated with immunosuppression, in contrast to the MITFhigh phenotype of T cell-edited tumor cells from late metastases. In summary, our study demonstrates that tumor recurrences after long-term latency develop towards T-cell resistance by independent genetic events, suggesting a mechanism of T cell-driven genetic evolution of melanoma as a means to evade immune recognition and tumor immunotherapy. Genetic alterations lead to loss of tumor antigen presentation. Cell lines were generated from tumor material, differences in T cell recognition were observed and Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from the cell lines. SNP analysis of different melanoma cell lines obtained from one melanoma patient (4 cell lines from different metastasis of one patient with matching germline DNA).

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Identification of drug resistance genes in melanoma

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