Show Notes
Pepe D et al., The American Journal of Human Genetics (112:1–21, June 5, 2025) - Pepe et al. show that annotating cancer mutations to the transcripts actually expressed in tumors uncovers previously overlooked non-coding promoter mutations in melanoma. Using TCGA mutation calls, RNA-seq, and an automated Salmon+VEP pipeline, they reclassify multiple hotspots and validate functional effects for IRF3/BCL2L12 and KNSTRN promoter mutations with CRISPR-Cas9 and reporter assays. Key terms: melanoma, non-coding mutations, synonymous mutations, transcript annotation, CRISPR-Cas9.
Study Highlights:
The authors reannotated TCGA melanoma mutation clusters to expressed transcripts and found that 22% (11/50) of identified clusters previously labeled as coding are non-coding promoter mutations. They validated IRF3/BCL2L12 promoter mutations in isogenic CRISPR-Cas9 Mel-ST models and reporter assays, showing reduced IRF3, BCL2L12, and downstream TP53 expression. KNSTRN and SLC27A5 clusters were also reclassified as promoter mutations, and transcription-factor binding analyses implicate disruption of ETS/SP/E2F sites. The study presents a simple Salmon+VEP workflow to improve mutation annotation and notes an association between IRF3/BCL2L12 promoter mutations and poorer immunotherapy response.
Conclusion:
Integrating RNA-seq expression data into mutation annotation reveals functional non-coding promoter mutations missed by reference-transcript annotation; a Salmon+VEP reannotation workflow improves accuracy and highlights clinically relevant non-coding events in melanoma.
QC:
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Metadata checks passed: 5.
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QC result: Pass.
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Article title:
Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma
First author:
Pepe D
Journal:
The American Journal of Human Genetics (112:1–21, June 5, 2025)
DOI:
https://doi.org/10.1016/j.ajhg.2025.04.005
Reference:
Pepe D., Janssens X., Timcheva K., et al. Reannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma. The American Journal of Human Genetics 112, 1–21 (June 5, 2025). https://doi.org/10.1016/j.ajhg.2025.04.005
License:
CC BY 4.0 (http://creativecommons.org/licenses/by/4.0/)
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