OCT 12, 2017 12:00 PM PDT

Comprehensive genomic and transcriptomic analysis of acral melanoma: A path towards therapeutic development

Speaker
  • Assistant Professor, Integrated Cancer Genomics Division, Collaborative Sequencing Center Director, Scientific Operations, TGen
    Biography
      Dr. Liang is Director of the Collaborative Sequencing Center (CSC), Assistant Professor in the Integrated Cancer Genomics and Neurogenomics Divisions, and Director of Scientific Operations at TGen. In 2010, Dr. Liang led the creation of the CSC, which acts as TGen's primary next-generation sequencing resource through collaborative projects. Since its inception, the CSC has completed over 320 projects and has generated over 120Tb of raw sequencing data for studies encompassing a wide spectrum of diseases including pancreatic cancer, cholangiocarcinoma, cutaneous and acral melanomas, Sézary syndrome, breast cancer, Alzheimer's disease, diffuse large B-cell lymphoma, and breast cancer. The CSC has been involved in numerous studies including the SU2C Genomics-Enabled Medicine for Melanoma trial and an acral melanoma study funded by the Melanoma Research Alliance. It is also involved in a longitudinal Multiple Myeloma Research Foundation (MMRF) study along with clinical sequencing studies. Through projects such as these, Dr. Liang is actively in cancer genomics research and the application of next generation sequencing capabilities to unearth somatic variants associated with disease. She is also the genomics lead on a pediatric diffuse intrinsic pontine glioma (DIPG) precision medicine clinical trial with UCSF and PNOC (Pediatric Neuro-Oncology Consortium). Through the Neurogenomics division, Dr. Liang is actively involved in cell-specific transcriptomic characterizations in Alzheimer's disease in order to understand cell-specific contributions to pathogenesis, as well as tuberous sclerosis research in an effort to investigate the molecular basis for phenotypic variability in patients. Ms. Liang received her Bachelor of Science in Biological Sciences (Computational Biology Option) from Carnegie Mellon University, and her Ph.D. from Arizona State University in Molecular and Cellular Biology.

    Abstract

    Acral lentiginous melanoma (ALM) is a rare sun-shielded melanoma subtype associated with worse survival than cutaneous melanoma (CM), a more common form of skin cancer linked to exposure to ultra-violet (UV) light. In order to better understand the genomic landscape of ALM with the goal of identifying novel therapeutic strategies, we performed comprehensive genomic and transcriptomic analysis of 37 tumors from 34 clinically well-annotated, histopathologically qualified ALM patients. For all samples with available analytes, whole exome sequencing, long insert whole genome and mRNA sequencing was performed. Bioinformatics tools and workflows were used to identify somatic point mutations, indels, copy number alterations, structural variants, and to perform gene expression analyses. The overall mutation burden (SNV) was variable, with a median of 123 SNVs (range of 2-2449), including 16 samples with < 100. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. Our study thus demonstrates the value of implementing a comprehensive sequencing and informatics strategy to understand the genomics of a disease and how such integrated analyses have the power to lead to identifying therapeutic strategies for patients. 

     


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