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Clustered somatic mutations are frequent in transcription factor binding motifs within proximal promoter regions in melanoma and other cutaneous malignancies

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posted on 2023-03-13, 04:54 authored by AJ Colebatch, L Di Stefano, SQ Wong, RD Hannan, PM Waring, Alexander DobrovicAlexander Dobrovic, GA McArthur, AT Papenfuss
Most cancer DNA sequencing studies have prioritized recurrent non-synonymous coding mutations in order to identify novel cancer-related mutations. Although attention is increasingly being paid to mutations in non-coding regions, standard approaches to identifying significant mutations may not be appropriate and there has been limited analysis of mutational clusters in functionally annotated noncoding regions. We sought to identify clustered somatic mutations (hotspot regions across samples) in functionally annotated regions in melanoma and other cutaneous malignancies (cutaneous squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma). Sliding window analyses revealed numerous recurrent clustered hotspot mutations in proximal promoters, with some specific clusters present in up to 25% of cases. Mutations in melanoma were clustered within ETS and Sp1 transcription factor binding motifs, had a UV signature and were identified in other cutaneous malignancies. Clinicopathologic correlation and mutation analysis support a causal role for chronic UV irradiation generating somatic mutations in transcription factor binding motifs of proximal promoters.


AC was supported by a National Health and Medical Research Council (NHMRC) Centre for Research Excellence Grant. ATP was supported by a NHMRC Program Grant [1054618] and the Lorenzo and Pamela Galli Charitable Trust. GM was supported by the Lorenzo and Pamela Galli Charitable Trust and NHMRC Program Grant [1053792] and Fellowships [1002654; 1106576]. GM and AD are principal investigators on The Melbourne Melanoma Project which is supported by the Victorian Government through the Victorian Cancer Agency Translational Research Program and established through support of the Victor Smorgon Charitable Fund. The work benefited from support by the Victorian State Government Operational Infrastructure Support to the Peter Mac and the ONJCRI, and the Australian Government NHMRC Independent Research Institute Infrastructure Support Scheme.


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© 2016 The Authors. This is an open access article under the CC BY license (

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