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      Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

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          Abstract

          We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1 P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1 P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

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          Most cited references 81

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            Fast and accurate short read alignment with Burrows–Wheeler transform

            Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk
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              Coot: model-building tools for molecular graphics

              CCP4mg is a project that aims to provide a general-purpose tool for structural biologists, providing tools for X-ray structure solution, structure comparison and analysis, and publication-quality graphics. The map-fitting tools are available as a stand-alone package, distributed as 'Coot'.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                9 July 2012
                29 July 2012
                September 2012
                01 March 2013
                : 44
                : 9
                : 1006-1014
                Affiliations
                [1 ]Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
                [2 ]Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut, USA
                [3 ]W.M. Keck Foundation Biotechnology Resource Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA
                [4 ]Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
                [5 ]Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, USA
                [6 ]Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA
                [7 ]Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA
                [8 ]Department of Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
                [9 ]Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
                [10 ]Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
                [11 ]Comprehensive Cancer Center, Section of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USA
                [12 ]Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut, USA
                [13 ]Department of Ophthalmology, Yale University School of Medicine, New Haven, Connecticut, USA
                [14 ]Department of Medicine, Division of Dermatology, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, USA
                [15 ]Center for Human Genetics and Genomics, Yale University School of Medicine, New Haven, Connecticut, USA
                [16 ]Program on Neurogenetics, Yale University School of Medicine, New Haven, Connecticut, USA
                [17 ]School of Public Health, Yale University School of Medicine, New Haven, Connecticut, USA
                Author notes
                Correspondence should be addressed to R.H. ( ruth.halaban@ 123456yale.edu )
                Article
                NIHMS390374
                10.1038/ng.2359
                3432702
                22842228
                © 2012 Nature America,Inc. All rights reserved.

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA121974 || CA
                Categories
                Article

                Genetics

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