Systematic genomic and translational efficiency studies of uveal melanoma

To further our understanding of the somatic genetic basis of uveal melanoma, we sequenced the protein-coding regions of 52 primary tumors and 3 liver metastases together with paired normal DNA. Known recurrent mutations were identified in GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. The role of mutated EIF1AX was tested using loss of function approaches including viability and translational efficiency assays. Knockdown of both wild type and mutant EIF1AX was lethal to uveal melanoma cells. We probed the function of N-terminal tail EIF1AX mutations by performing RNA sequencing of polysome-associated transcripts in cells expressing endogenous wild type or mutant EIF1AX. Ribosome occupancy of the global translational apparatus was sensitive to suppression of wild type but not mutant EIF1AX. Together, these studies suggest that cells expressing mutant EIF1AX may exhibit aberrant translational regulation, which may provide clonal selective advantage in the subset of uveal melanoma that harbors this mutation.

[1]  B. Taylor,et al.  Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma , 2016, Nature Genetics.

[2]  A. Enk,et al.  Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma , 2015, PloS one.

[3]  J. Wolchok,et al.  Genetic basis for clinical response to CTLA-4 blockade in melanoma. , 2014, The New England journal of medicine.

[4]  Steven J. M. Jones,et al.  Integrated Genomic Characterization of Papillary Thyroid Carcinoma , 2014, Cell.

[5]  Ellen T. Gelfand,et al.  Parallel genome-scale loss of function screens in 216 cancer cell lines for the identification of context-specific genetic dependencies , 2014, Scientific Data.

[6]  C. Emery,et al.  Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations , 2014, Oncogene.

[7]  Kang Zhang,et al.  Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. , 2014, Cancer cell.

[8]  G. Merlino,et al.  Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. , 2014, Cancer cell.

[9]  C. Emery,et al.  Landscape of genetic alterations in patients with metastatic uveal melanoma. , 2014 .

[10]  C. Roberts,et al.  Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers , 2014, Proceedings of the National Academy of Sciences.

[11]  W. Hahn,et al.  Residual Complexes Containing SMARCA2 (BRM) Underlie the Oncogenic Drive of SMARCA4 (BRG1) Mutation , 2014, Molecular and Cellular Biology.

[12]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[13]  A. Giobbie-Hurder,et al.  Clinical activity of ipilimumab for metastatic uveal melanoma , 2013, Cancer.

[14]  David Gentien,et al.  SF3B1 mutations are associated with alternative splicing in uveal melanoma. , 2013, Cancer discovery.

[15]  J. Yokota,et al.  A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. , 2013, Cancer research.

[16]  N. Ban,et al.  The crystal structure of the eukaryotic 40S ribosomal subunit in complex with eIF1 and eIF1A , 2013, Nature Structural &Molecular Biology.

[17]  T. Steitz,et al.  The initiation of mammalian protein synthesis and the mechanism of scanning , 2013, Nature.

[18]  A. Hinnebusch,et al.  Exome sequencing identifies recurrent somatic mutations in EIF1AX and SF3B1 in uveal melanoma with disomy 3 , 2013, Nature Genetics.

[19]  Catherine J. Wu,et al.  SF3B1 mutations in chronic lymphocytic leukemia. , 2013, Blood.

[20]  G. Crabtree,et al.  Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy , 2013, Nature Genetics.

[21]  A. Bowcock,et al.  Recurrent mutations at codon 625 of the splicing factor SF3B1 in uveal melanoma , 2013, Nature Genetics.

[22]  A. McKenna,et al.  Evolution and Impact of Subclonal Mutations in Chronic Lymphocytic Leukemia , 2012, Cell.

[23]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer-associated genes , 2013 .

[24]  B. Hemmings,et al.  Translation regulation as a therapeutic target in cancer. , 2012, Cancer research.

[25]  S. Woodman,et al.  Combination Small Molecule MEK and PI3K Inhibition Enhances Uveal Melanoma Cell Death in a Mutant GNAQ- and GNA11-Dependent Manner , 2012, Clinical Cancer Research.

[26]  A. McKenna,et al.  Absolute quantification of somatic DNA alterations in human cancer , 2012, Nature Biotechnology.

[27]  D. Sabatini,et al.  A unifying model for mTORC1-mediated regulation of mRNA translation , 2012, Nature.

[28]  S. Woodman,et al.  Genetic and molecular characterization of uveal melanoma cell lines , 2012, Pigment cell & melanoma research.

[29]  S. Woodman.  Metastatic Uveal Melanoma: Biology and Emerging Treatments , 2012, Cancer journal.

[30]  Nicholas T. Ingolia,et al.  The translational landscape of mTOR signalling steers cancer initiation and metastasis , 2012, Nature.

[31]  A. Bowcock,et al.  Frequent Mutation of BAP1 in Metastasizing Uveal Melanomas , 2010, Science.

[32]  J. O'Brien,et al.  Mutations in GNA11 in uveal melanoma. , 2010, The New England journal of medicine.

[33]  S. Formenti,et al.  Translational control in cancer , 2010, Nature Reviews Cancer.

[34]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[35]  G. Barsh,et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi , 2010 .

[36]  A. Hinnebusch,et al.  Regulatory elements in eIF1A control the fidelity of start codon selection by modulating tRNA(i)(Met) binding to the ribosome. , 2010, Genes & development.

[37]  M. Robinson,et al.  A scaling normalization method for differential expression analysis of RNA-seq data , 2010, Genome Biology.

[38]  D. Sacks,et al.  IQGAPs in cancer: A family of scaffold proteins underlying tumorigenesis , 2009, FEBS letters.

[39]  Nicholas T. Ingolia,et al.  Genome-Wide Analysis in Vivo of Translation with Nucleotide Resolution Using Ribosome Profiling , 2009, Science.

[40]  E. Simpson,et al.  Frequent somatic mutations of GNAQ in uveal melanoma and blue nevi , 2008, Nature.

[41]  Mikkel A. Algire,et al.  The eukaryotic translation initiation factors eIF1 and eIF1A induce an open conformation of the 40S ribosome. , 2007, Molecular cell.

[42]  Jon R Lorsch,et al.  N‐ and C‐terminal residues of eIF1A have opposing effects on the fidelity of start codon selection , 2007, The EMBO journal.

[43]  A. de Klein,et al.  Clinical and cytogenetic analyses in uveal melanoma. , 2006, Investigative ophthalmology & visual science.

[44]  Arun D. Singh,et al.  Uveal melanoma: epidemiologic aspects. , 2005, Ophthalmology clinics of North America.

[45]  A. Hinnebusch,et al.  Domains of eIF1A that mediate binding to eIF2, eIF3 and eIF5B and promote ternary complex recruitment in vivo , 2003, The EMBO journal.

[46]  O. Larsson,et al.  Concomitant loss of chromosome 3 and whole arm losses and gains of chromosome 1, 6, or 8 in metastasizing primary uveal melanoma. , 2001, Investigative ophthalmology & visual science.

[47]  O. Meyuhas.  Synthesis of the translational apparatus is regulated at the translational level. , 2000, European journal of biochemistry.

[48]  G. Wagner,et al.  The eIF1A solution structure reveals a large RNA-binding surface important for scanning function. , 2000, Molecular cell.

[49]  C. Hellen,et al.  Eukaryotic ribosomes require initiation factors 1 and 1A to locate initiation codons , 1998, Nature.

[50]  N. Bornfeld,et al.  Prognostic implications of monosomy 3 in uveal melanoma , 1996, The Lancet.

[51]  N. Bornfeld,et al.  Cytogenetics of twelve cases of uveal melanoma and patterns of nonrandom anomalies and isochromosome formation. , 1995, Cancer genetics and cytogenetics.

[52]  D. Horsman,et al.  Cytogenetic analysis of uveal melanoma consistent occurrence of monosomy 3 and trisomy 8q , 1993, Cancer.

[53]  R. Glynn,et al.  Survival of patients with metastases from uveal melanoma. , 1991, Ophthalmology.

[54]  Sozen,et al.  Mutations in GNA 11 in Uveal Melanoma , 2022 .