biostudies-literatureUnknown112(6)Pepe DThe role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%-5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory factoAmerican journal of human genetics1447-1467https://www.ebi.ac.uk/biostudies/studies/S-EPMC12256795biostudies-literatureReannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.PMC12256795Godderis ACabrerizo Granados DKonstantakos VDe Groote DKampen KRDewaele BRoyaert JMarron-Linares GMPepe DTimcheva KMenschaert GVerhasselt ACools CSubramanian KFranco-Tolsau MDe Keersmaecker KDe Bie JVerbeeck JJanssens XVerbelen BfalseReannotation of cancer mutations based on expressed RNA transcripts reveals functional non-coding mutations in melanoma.The role of synonymous mutations in cancer pathogenesis is currently underexplored. We developed a method to detect significant clusters of synonymous and missense mutations in public cancer genomics data. In melanoma, we show that 22% (11/50) of these mutation clusters are misannotated as coding mutations because the reference transcripts used for their annotation are not expressed. Instead, these mutations are actually non-coding. This, for instance, applies to the mutation clusters targeting known cancer genes kinetochore localized astrin (SPAG5) binding protein (KNSTRN) and BCL2-like 12 (BCL2L12), each affecting 4%-5% of melanoma tumors. For the latter, we show that these mutations are functional non-coding mutations that target the shared promoter region of interferon regulatory facto2025-01-01T00:00:00Z2025 Jun2026-03-10T23:13:53.688Z2025-08-13T03:04:14.01ZS-EPMC122567954035993810.1016/j.ajhg.2025.04.005