Frequent DPH3 promoter mutations in skin cancers

Area of Science:

• Genomics
• Cancer Biology
• Dermatology

Background:

• Recent studies indicate cancer-associated somatic mutations frequently occur in genomic regulatory elements.
• Understanding mutations in non-coding regions is crucial for cancer research.

Purpose of the Study:

• To investigate the frequency and characteristics of somatic mutations in the bidirectional promoter of DPH3 and OXNAD1 genes in skin cancers.
• To assess the potential functional impact of these mutations on gene expression.

Main Methods:

• Exome sequencing of 21 melanomas.
• Follow-up screening of 586 skin lesions (melanoma, BCC, SCC, nevi).
• Reporter assays in a melanoma cell line.

Main Results:

• Frequent somatic mutations were identified in the DPH3/OXNAD1 promoter in melanoma, BCC, and SCC, with UV-signature characteristics.
• Mutations were found adjacent to and within an Ets/TCF binding motif.
• Reporter assays showed increased promoter activity with specific mutations, but no observed effect on gene transcription in tumors.

Conclusions:

• The study demonstrates frequent occurrence of non-coding somatic mutations in the DPH3/OXNAD1 promoter in major skin cancers.
• These mutations, exhibiting UV signatures, are located near Ets transcription factor binding sites.
• The functional consequences of these promoter mutations on DPH3 and OXNAD1 transcription in vivo remain to be elucidated.