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

2013; National Academy of Sciences; Volume: 110; Issue: 33 Linguagem: Inglês

10.1073/pnas.1304227110

1091-6490

Jared J. Gartner, Stephen C. J. Parker, Todd D. Prickett, Ken Dutton‐Regester, Michael L. Stitzel, Jimmy Lin, Sean Davis, Vijaya L. Simhadri, Sujata Jha, Nobuko Katagiri, Valer Gotea, Jamie K. Teer, Xiaomu Wei, Mario A. Morken, Umesh Bhanot, Chen Guo, Laura Elnitski, Michael A. Davies, Hui Shen, Hannah Carter, Rachel Karchin, William H. Robinson, Steven E. Robinson, Steven A. Rosenberg, Francis S. Collins, Giovanni Parmigiani, Anton A. Komar, Chava Kimchi‐Sarfaty, Nicholas K. Hayward, Elliott H. Margulies, Yardena Samuels, Jesse Becker, Betty Benjamin, Robert W. Blakesley, Gerry Bouffard, Shelise Brooks, Holly Coleman, Mila Dekhtyar, Michael D. Gregory, Xiaobin Guan, Jyoti Gupta, Joel Han, April Hargrove, Shi-ling Ho, Taccara Johnson, Richelle Legaspi, Sean Lovett, Quino Maduro, Cathy Masiello, Baishali Maskeri, Jenny McDowell, Casandra Montemayor, James C. Mullikin, Morgan Park, Nancy L. Riebow, Karen Schandler, Brian Schmidt, Christina Sison, Mal Stantripop, James Thomas, Pam Thomas, Meg Vemulapalli, Alice Young,

vaccines and immunoinformatics approaches

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.