21 Apr Targeted Melanoma Panel Identifies Genetic Subsets of Melanoma
Medical Research: What is the background for this study? What are the main findings?
Dr. Wilson: Metastatic cutaneous melanoma is an extremely aggressive form of skin cancer. Traditionally, it has been characterized by clinicopathologic characteristics. More recently, melanoma tumors have also been stratified by common somatic mutations for which targeted therapies have been developed or are under investigation, including BRAF, NRAS and KIT. In addition to somatic mutations, aberrant intracellular signaling pathways and cell cycle disruption contribute to melanoma pathogenesis. Indeed, recent next generation sequencing studies have identified a number of new genes involved in melanomagenesis. A comprehensive evaluation and understanding of concurrent and mutually exclusive mutations in tumors has been lacking. Therefore, we developed a comprehensive custom targeted capture of 108 genes previously implicated in melanoma pathogenesis. We used the targeted panel to perform massively parallel sequencing on 94 well-established human melanoma cell lines, 67 patient-derived xenografts (PDX), and 5 cell lines made from PDX, all untreated.
Samples were clustered based on deleterious mutations. Eighty-three percent of samples had deleterious mutations in the MAPK signaling pathway (including BRAF, RAS) and NF1. Ten percent of samples had PI3K pathway mutations which were predominantly associated with BRAF mutations. TP53 was found to be mutated in 24% of the samples and were also associated with mutations in the MAPK pathway. Mutations in chromatin remodeling genes were mutually exclusive with each other, but were associated with BRAF and NRAS mutations. Of particular interest, five of the 10 NF1mutated samples harbored likely deleterious mutations in MAP3K5 or MAP3K9, suggesting the potential involvement of JNK signal transduction pathway in a cohort of samples.
Medical Research: What should clinicians and patients take away from your report?
Dr. Wilson: This study provides a comprehensive examination of melanoma genetics and provides novel insights in addition to the known, prevalent somatic mutations which identify melanoma tumors currently. Of course, functional studies are needed to confirm the biology of these genetic observations.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Wilson: It will be important to evaluate these novel genetic subsets in tumor samples from melanoma patients. In addition, correlation of these novel genetic subsets with clinicopathologic characteristics and response to treatment is imperative. Identification of a genetic profile for melanoma tumors has potential implications for treatment decisions.
4668: Targeted, massively parallel sequencing identifies novel genetic subsets of cutaneous melanoma
Tuesday, Apr 21, 2015
Bradley Garman1, Clemens Krepler2, Katrin Sproesser2, Patrica Brafford2, Melissa Wilson3, Bradley Wubbenhorst1, Ravi Amaravadi4, Joseph Bennett5, Marilda Beqiri2, Michael Davies6, David Elder4, Keith Flaherty7, Dennie Frederick7, Tara C. Gangadhar4, Michael Guarino5, David Hoon8, Giorgos Karakousis4, Nandita Mitra1, Nicholas J. Petrelli5, Lynn Schuchter4, Batool Shannan2, Jennifer Wargo6, Min Xiao2, Wei Xu4, Xaiowei Xu4, Meenhard Herlyn2, Katherine Nathanson1. 1Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; 2The Wistar Institute, Melanoma Research Center, Philadelphia, PA; 3Perlmutter Cancer Center, NYU School of Medicine, NYU Langone Medical Center, New York, NY; 4University of Pennsylvania Abramson Cancer Center, Philadelphia, PA; 5Helen F. Graham Cancer Center, Newark, DE; 6MD Anderson Cancer Center, Houston, TX; 7Massachusetts General Hospital, Boston, MA; 8John Wayne Cancer Institute, Santa Monica, CA
MedicalResearch.com Interview with: Melissa Wilson, MD, PhD (2015). Targeted Melanoma Panel Identifies Genetic Subsets of Melanoma