Our primary research interests are the study of the genes that are altered in cancer and the cellular pathways these genes perturb. Identifying the genetic alterations and understanding how they work provides the foundation for novel approaches to the prevention, diagnosis and treatment of cancer. To fulfill these goals, we are using a sequence-based mutational analysis to evaluate genetic alterations in cutaneous malignant melanoma. Melanoma develops from the malignant transformation of melanocytes. It is the most common fatal skin cancer, and its incidence has increased at a more rapid rate than any other malignancy in the US. Unlike early-stage disease, late stage melanoma has few therapeutic options;hence our studies focus on late stage disease. The clinical progression is assumed to correspond to the accumulation of genetic mutations. In order to develop treatments for advanced disease, it is important to understand the genetic alterations leading to melanoma as such understanding will permit personalized design of treatments for melanoma. For this project, we have established a tumor bank, which we use as a source of genomic DNA. In order to determine the quality of the tumor bank a few strategies have been employed: a. Cytopatholgy is used to determine the percentage of melanoma cells within the sample provided. Only samples that include at least 75% melanoma-derived cells qualify, to ensure that non-neoplastic cells within the tumors do not complicate the analysis. b. To verify that we can detect mutations in tumor DNA, we sequence commonly known oncogenic mutations in metastatic melanoma such BRAF and NRAS. Using 80 samples from our tumor bank we have discovered novel mutations in the transcription factor MITF, in matrix metalloproteinase genes including MMP-8 as well as in protein tyrosine kinases such as ERBB4. Furthermore, whole exome analysis of 14 melanoma cases has identified a novel recurrent mutation in TRRAP as well as a novel highly mutated gene-GRIN2A. These results have been pursued using several avenues: a. The discovered mutations were cloned and were found to have functional effects. b. We are conducting a clinical trial based on the identified ERBB4 mutations found in melanoma patients and treatment with the FDA approved drug lapatinib. Our work provides a strong rationale for development of therapeutic and diagnostic approaches for individuals harboring the various discovered mutations. Using these tools, one could envision tailored therapeutics based on the mutations in an individuals cancer.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2012
Total Cost
$1,187,324
Indirect Cost
Name
National Human Genome Research Institute
Department
Type
DUNS #
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Prickett, Todd D; Zerlanko, Brad; Gartner, Jared J et al. (2014) Somatic mutations in MAP3K5 attenuate its proapoptotic function in melanoma through increased binding to thioredoxin. J Invest Dermatol 134:452-60
Robbins, Paul F; Lu, Yong-Chen; El-Gamil, Mona et al. (2013) Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 19:747-52
Lu, Yong-Chen; Yao, Xin; Li, Yong F et al. (2013) Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol 190:6034-42
Hansen, Nancy F; Gartner, Jared J; Mei, Lan et al. (2013) Shimmer: detection of genetic alterations in tumors using next-generation sequence data. Bioinformatics 29:1498-503
Hill, Victoria K; Gartner, Jared J; Samuels, Yardena et al. (2013) The genetics of melanoma: recent advances. Annu Rev Genomics Hum Genet 14:257-79
Walia, Vijay; Mu, Euphemia W; Lin, Jimmy C et al. (2012) Delving into somatic variation in sporadic melanoma. Pigment Cell Melanoma Res 25:155-70
Prickett, Todd D; Samuels, Yardena (2012) Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res 18:4240-6
Parker, Stephen C J; Gartner, Jared; Cardenas-Navia, Isabel et al. (2012) Mutational signatures of de-differentiation in functional non-coding regions of melanoma genomes. PLoS Genet 8:e1002871
Gartner, Jared J; Davis, Sean; Wei, Xiaomu et al. (2012) Comparative exome sequencing of metastatic lesions provides insights into the mutational progression of melanoma. BMC Genomics 13:505
Prickett, Todd D; Wei, Xiaomu; Cardenas-Navia, Isabel et al. (2011) Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma. Nat Genet 43:1119-26

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