Clustered somatic mutations are frequent in transcription factor binding motifs within proximal promoter regions in melanoma and other cutaneous malignancies.
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.
Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Victoria, Australia.|Department of Pathology, University of Melbourne, Victoria, Australia.
Andrew J
AJ
Colebatch
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Leon
L
Di Stefano
Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Victoria, Australia.
Stephen Q
SQ
Wong
ACRF Department of Cancer Biology and Therapeutics, John Curtin School of Medical Research, The Australian National University, Australian Capital Territory, Australia.
Ross D
RD
Hannan
Department of Pathology, University of Melbourne, Victoria, Australia.
Paul M
PM
Waring
Department of Pathology, University of Melbourne, Victoria, Australia.|Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Victoria, Australia.|School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
Alexander
A
Dobrovic
Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Victoria, Australia.|Department of Pathology, University of Melbourne, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
Grant A
GA
McArthur
Research Division, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Victoria, Australia.|Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Victoria, Australia.
Anthony T
AT
Papenfuss
D020816:Amino Acid Motifs; D002280:Basal Cell Carcinoma / Q000235:genetics; D015266:Carcinoma, Merkel Cell / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000235:genetics*
D050783:Proto-Oncogene Proteins c-ets; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human
gene promoter; melanoma; non-coding mutations; transcription factors; ultraviolet radiation