title: Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma.
abstract: Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies.
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Gartner
authors.forename: Stephen C J
authors.initials: SC
authors.lastname: Parker
authors.forename: Todd D
authors.initials: TD
authors.lastname: Prickett
authors.forename: Ken
authors.initials: K
authors.lastname: Dutton-Regester
authors.forename: Michael L
authors.initials: ML
authors.lastname: Stitzel
authors.forename: Jimmy C
authors.initials: JC
authors.lastname: Lin
authors.forename: Sean
authors.initials: S
authors.lastname: Davis
authors.forename: Vijaya L
authors.initials: VL
authors.lastname: Simhadri
authors.forename: Sujata
authors.initials: S
authors.lastname: Jha
authors.forename: Nobuko
authors.initials: N
authors.lastname: Katagiri
authors.forename: Valer
authors.initials: V
authors.lastname: Gotea
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Teer
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.forename: Mario A
authors.initials: MA
authors.lastname: Morken
authors.forename: Umesh K
authors.initials: UK
authors.lastname: Bhanot
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.forename: Laura L
authors.initials: LL
authors.lastname: Elnitski
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: William
authors.initials: W
authors.lastname: Robinson
authors.forename: Steven
authors.initials: S
authors.lastname: Robinson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Anton A
authors.initials: AA
authors.lastname: Komar
authors.forename: Chava
authors.initials: C
authors.lastname: Kimchi-Sarfaty
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.forename: Elliott H
authors.initials: EH
authors.lastname: Margulies
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D016086:Lentivirus; D008545:Melanoma / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C430100:BCL2L12 protein, human; D017931:DNA Primers; D035683:MicroRNAs; D009124:Muscle Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53
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