Abstract
Seborrheic keratoses are common benign epidermal lesions that are associated with increased age and sun-exposure. Those lesions despite harboring multiple somatic alterations in contrast to malignant tumors appear to be genetically stable. In order to investigate and characterize the presence of recurrent mutations, we performed exome sequencing on DNA from one seborrheic keratosis lesion and corresponding blood cells from the same patients with follow up investigation of alterations identified by exome sequencing in 24 additional lesions from as many patients. In addition we investigated alterations in all lesions at specific genes loci that included FGFR3, PIK3CA, HRAS, BRAF, CDKN2A and TERT and DHPH3 promoters. The exome sequencing data indicated three mutations per Mb of the targeted sequence. The mutational pattern depicted typical UV signature with majority of alterations being C>T and CC>TT base changes at dipyrimidinic sites. The FGFR3 mutations were the most frequent, detected in 12 of 25 (48%) lesions, followed by the PIK3CA (32%), TERT promoter (24%) and DPH3 promoter mutations (24%). TERT promoter mutations associated with increased age and were present mainly in the lesions excised from head and neck. Three lesions also carried alterations in CDKN2A. FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; however, increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression. Thus, in this study we report overall mutation rate through exome sequencing and show the most frequent mutations seborrheic keratosis.
Highlights
Seborrheic keratoses represent one of the most common benign epidermal tumors that associate with increased age [1]
FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression
We investigated seborrheic keratoses for alterations in genes that play a role in the development (FGFR3, PIK3CA, HRAS) and or those that are frequent in other skin neoplasms (BRAF, CDKN2A)
Summary
Seborrheic keratoses represent one of the most common benign epidermal tumors that associate with increased age [1]. The majority of seborrheic keratoses are monoclonal tumors, representing autonomous neoplasia resulting from clonal expansion of somatically mutated cells rather than epidermal hyperplasia [5]. Seborrheic keratoses appear to be genetically stable but harbor multiple somatic alterations [6]. Despite lack of malignant potential, 89 percent of the lesions carry at least one and 45 percent more than one mutation in a well characterized oncogene [6, 7]. Seborrheic keratosis, despite being hyper-proliferative remain well differentiated and rather than senescence due to oncogenic signals, a positive feedback loop between FGFR3 and the transcription factor FOXN1 has been suggested to prevent malignant progression of those lesions [6, 10, 11]
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