Clustered somatic mutations are frequent in transcription factor binding motifs within proximal promoter regions in melanoma and other cutaneous malignancies
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Andrew J. Colebatch1,2, Leon Di Stefano3, Stephen Q. Wong1, Ross D. Hannan4, Paul M. Waring2, Alexander Dobrovic2,5,6, Grant A. McArthur1,2,7,*, Anthony T. Papenfuss1,3,7,8,*
1 Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Victoria, Australia
2 Department of Pathology, University of Melbourne, Victoria, Australia
3 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
4 ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Australian Capital Territory, Australia
5 Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Victoria, Australia
6 School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia
7 Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia
8 Department of Medical Biology, University of Melbourne, Victoria, Australia
* These authors have contributed equally to this work
Andrew J. Colebatch, email:
Anthony T. Papenfuss, email:
Keywords: melanoma, gene promoter, non-coding mutations, transcription factors, ultraviolet radiation
Received: July 29, 2016 Accepted: August 30, 2016 Published: September 07, 2016
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 non-coding 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.
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