HomeResearchIntramural ResearchResearch Branches at NHGRICancer Genetics Branch Samuels Lab

Yardena Samuels, Ph.D. Investigator Cancer Genetics Branch Head Molecular Cancer Genetics Section B.Sc. Cambridge University, United Kingdom, 1993 M.Sc. Hebrew University of Jerusalem, Israel, 1997 Ph.D. Ludwig Institute for Cancer Research, United Kingdom, 2002 (301) 451-2628 (301) 594-0023 samuelsy@mail.nih.gov Building 50, Room 5140 50 South Dr, MSC 8000 Bethesda, MD 20892-8000 Selected Publications Postdoctoral Fellowships in Cancer Genetics and Molecular Biology

Genetic alterations, including point mutations, deletions, and amplifications, occur in every cancer cell. These changes are known to occur in oncogenes, tumor suppressor genes, and stability genes. Although many of these genes have been identified for certain types of tumors, most remain to be discovered. Dr. Samuels uses high-throughput DNA sequencing and whole-genome genotyping to identify novel mutations in gene families that regulate signal transduction in late-stage cutaneous melanoma.

Melanomas arise as a result of the malignant transformation of melanocytes, the pigment-producing cells located in the bottom layer of human skin. It is the most common fatal skin cancer, and its incidence has increased 15-fold in the United States over the last 40 years, faster than any other malignancy. Each year in the United States, nearly 60,000 people are diagnosed with malignant melanomas and more than 8,000 will die of the disease.

As melanomas penetrate farther into the skin, treatment options, cure rates, and survival rates decrease. In early stage disease, the tumor is in its radial growth phase (RGP) and stays on the skin's surface. These tumors can usually be completely removed by simple surgery. Once the malignancy switches to the vertical growth phase (VGP), it penetrates through the skin and is able to metastasize to the lymph nodes and other sites in the body, rendering standard surgical interventions ineffective. Five-year survival rates for VGP melanoma range from 13 to 69 percent, and no treatment has yet been found to be universally effective.

Melanoma disease progression is assumed to be associated with the accumulation of genetic mutations over time. The genes that have already been implicated in the development of melanomas include CDKN2A, NRAS and BRAF. Dr. Samuels is using high-throughput DNA sequencing to search for additional mutated genes in melanoma. She is currently examining the genes encoding tyrosine and serine protein kinases, which play important roles in regulating the cellular events that lead to tumor formation; these genes are associated with a variety of human cancers and may be targets for therapeutic intervention. Identifying melanoma-associated genetic alterations in specific genes may eventually allow clinicians to understand the clinical progression of the disease, allowing them to better predict clinical course and therapeutic response. Dr. Samuels also hopes to identify new targets for drug development.

Dr. Samuels' earlier work has provided her strong expertise for these studies. Specifically, she previously used high-throughput DNA sequencing to analyze the phosphatidylinositol-3-kinase (PI3K) gene family, and discovered a large number of mutations associated with colorectal cancer in the lipid kinase-encoding gene PIK3CA. This gene is now known to be one of the most highly mutated oncogenes in human malignancies. PIK3CA plays an essential role in tumor cell proliferation, and is essential for invasion in vitro and metastasis in vivo. Treatment with the PI3K inhibitor LY294002 has been shown to reduce PIK3CA signaling and to preferentially inhibit the growth of cells producing mutant PIK3CA, suggesting that therapy directed at mutant PIK3CA or its downstream targets might be beneficial for some patients.

To identify genes regulated by mutant PIK3CA, Dr. Samuels performed serial analyses of gene expression (SAGE) and microarray analyses on cells containing either wild-type or mutant PIK3CA. She discovered that a gene called DDIT4 (also known as Redd1) was upregulated six- to ten-fold in all cells containing mutant PIK3CA (compared to cells contained wild-type PIK3CA). To examine the role of Redd1, which may be central to the PI3KCA pathway, Dr. Samuels is "knocking out" the Redd1 gene in human colorectal cancer cells that contain a mutant allele of PIK3CA, using homologous recombination techniques. She will then evaluate the effect of Redd1 inactivation by performing in vitro analyses of cell growth, migration, and invasion, and by studying in vivo models of metastatic disease. By doing so, she hopes to find new targets for clinical intervention, as well as gain new insights into basic tumor biology.

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Last Reviewed: December 2, 2008