Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma

Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13481-6. doi: 10.1073/pnas.1304227110. Epub 2013 Jul 30.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics*
  • Base Sequence
  • Blotting, Western
  • DNA Primers / genetics
  • Exome / genetics
  • Gene Expression Regulation / genetics*
  • Genetic Vectors / genetics
  • Genome, Human / genetics*
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Lentivirus
  • Melanoma / genetics*
  • MicroRNAs / genetics
  • Molecular Sequence Data
  • Muscle Proteins / genetics*
  • Muscle Proteins / metabolism
  • Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Proto-Oncogene Proteins c-bcl-2 / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • BCL2L12 protein, human
  • DNA Primers
  • MicroRNAs
  • Muscle Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53