Abstract A1-15: Systematic genomic characterization of uveal melanoma

Abstract

Abstract Uveal melanoma (UM) is a rare type of melanoma that occurs in the iris, ciliary body, and choroid of the eye. Metastatic disease is typically found in the liver and has no effective therapeutic options. To improve our understanding of the genetic drivers of UM, we sequenced the exome of 61 primary tumors and 3 liver metastases, each with matched normal DNA. Consistent with prior studies, the majority of UM tumors harbored mutually exclusive mutations in GNAQ and GNA11. Co-occurring with GNAQ and GNA11 mutations were inactivating mutations throughout the BAP1 coding region as well as recurrent mutations in the splicing factor SF3B1 and the translation initiation factor EIF1AX. Somatic mutations found only in metastatic tumor samples were also identified. The function of mutant EIF1AX was probed using loss of function experiments. Reduction of EIF1AX expression impaired the growth of both wild type and mutant cells. To identify transcripts regulated by EIF1AX at the level of translation, RNA sequencing of polysome-associated mRNAs was performed. Knockdown of wild type, but not mutant EIF1AX reduced the efficiency of ribosomal protein translation. Cancer cells expressing mutant EIF1AX may harbor changes in protein translation, which may be important for tumorigenesis. Citation Format: Chelsea S. Place, Ivana K. Kim, Bita Esmaeli, Ali Amin-Mansour, Daniel J. Treacy, Scott L. Carter, Eran Hodis, Nikhil Wagle, Sara Seepo, Xiaoxing Yu, Francisca Vazquez, Elizabeth Nickerson, Kristian Cibulskis, Aaron McKenna, Stacey B. Gabriel, Gad Getz, Eliezer M. Van Allen, Levi A. Garraway, Scott E. Woodman. Systematic genomic characterization of uveal melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-15.