Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing

• Published in: Nature communications Vol. 14; no. 1; p. 2702
• Main Authors: Selvam, Kathiresan, Sivapragasam, Smitha, Poon, Gregory M. K., Wyrick, John J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.05.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 631/208/211; 631/67/69; Binding sites; Cyclobutane; Cyclobutane pyrimidine dimers; Damage detection; Deoxyribonucleic acid; DNA; DNA Damage; ETS protein; Gene sequencing; Genomes; Humanities and Social Sciences; Humans; Kinases; Melanocytes; Melanocytes - metabolism; Melanoma; Melanoma - genetics; Melanoma - metabolism; multidisciplinary; Mutation; Nucleotides; Passengers; Proteins; Pyrimidine Dimers - genetics; RNA-directed DNA polymerase; Science; Science (multidisciplinary); Skin Neoplasms - genetics; Telomerase; Telomerase reverse transcriptase; Transcription factors; Ultraviolet Rays - adverse effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38265-3

Sequencing of melanomas has identified hundreds of recurrent mutations in both coding and non-coding DNA. These include a number of well-characterized oncogenic driver mutations, such as coding mutations in the BRAF and NRAS oncogenes, and non-coding mutations in the promoter of telomerase reverse transcriptase ( TERT ). However, the molecular etiology and significance of most of these mutations is unknown. Here, we use a new method known as CPD-capture-seq to map UV-induced cyclobutane pyrimidine dimers (CPDs) with high sequencing depth and single nucleotide resolution at sites of recurrent mutations in melanoma. Our data reveal that many previously identified drivers and other recurrent mutations in melanoma occur at CPD hotspots in UV-irradiated melanocytes, often associated with an overlapping binding site of an E26 transformation-specific (ETS) transcription factor. In contrast, recurrent mutations in the promoters of a number of known or suspected cancer genes are not associated with elevated CPD levels. Our data indicate that a subset of recurrent protein-coding mutations are also likely caused by ETS-induced CPD hotspots. This analysis indicates that ETS proteins profoundly shape the mutation landscape of melanoma and reveals a method for distinguishing potential driver mutations from passenger mutations whose recurrence is due to elevated UV damage. Genome sequencing has identified many recurrent mutations in melanoma. Here, we use targeted UV damage sequencing to show that many of these mutations are associated with UV damage hotspots that are linked to DNA binding by ETS transcription factors.