A recurring synonymous mutation in BCL2L12 was identified in 4% of metastatic melanomas.

  • Major finding: A recurring synonymous mutation in BCL2L12 was identified in 4% of metastatic melanomas.

  • Mechanism: Increased BCL2L12 accumulation due to reduced hsa-miR-651–5p binding inhibits UV-induced apoptosis.

  • Impact: Recurring synonymous mutations should not be overlooked in cancer genomics studies.

Synonymous mutations, or those that do not change the amino acid sequence of proteins, have generally been ignored in studies of cancer genomes, even though silent nucleotide substitutions have the potential to alter splicing, transcription, translation, or mRNA or protein stability. Gartner and colleagues performed whole-genome and whole-exome sequencing of 29 untreated metastatic melanomas and matched normal samples and identified 16 recurring synonymous mutations. Additional screening of 256 melanomas showed that a silent cytosine-to-thymine substitution in BCL2L12 was present in 4% of tumors overall. In the majority of melanoma samples, levels of mutant BCL2L12 mRNA and F17F “mutant” protein were significantly increased relative to the wild-type allele. This mutation did not create a splice site or known transcription factor binding site and did not affect translation or protein stability. However, the BCL2L12 mutation was predicted to disrupt binding of the microRNA hsa-miR-651-5p. Consistent with such a mechanism to increase transcript stability and subsequent protein accumulation, inhibition of hsa-miR-651-5p specifically increased levels of BCL2L12 mRNA in wild-type melanoma cells but had no effect on BCL2L12 expression in mutant cells. Given that BCL2L12 is known to bind p53 and inhibit apoptosis, these results raise the possibility that this synonymous BCL2L12 mutation may promote melanoma cell survival by increasing accumulation of BCL2L12. Indeed, knockdown of BCL2L12 selectively and significantly reduced cell viability and increased p53 target gene expression following ultraviolet radiation in BCL2L12-mutant melanoma cells, suggesting that the mutation confers resistance to p53-dependent apoptosis. The finding that a synonymous mutation can drive tumor growth underscores the potential clinical relevance of such mutations and indicates that they should receive attention in analyses of cancer genomic data.

Gartner JJ, Parker SC, Prickett TD, Dutton-Regester K, Stitzel ML, Lin JC, et al. Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma. Proc Natl Acad Sci U S A 2013;110:13481–6.

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