Oncotarget

Research Papers:

Genetic alterations in seborrheic keratoses

Barbara Heidenreich, Evygenia Denisova, Sivaramakrishna Rachakonda, Onofre Sanmartin, Timo Dereani, Ismail Hosen, Eduardo Nagore and Rajiv Kumar _

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Oncotarget. 2017; 8:36639-36649. https://doi.org/10.18632/oncotarget.16698

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Abstract

Barbara Heidenreich1, Evygenia Denisova1, Sivaramakrishna Rachakonda1, Onofre Sanmartin2, Timo Dereani1, Ismail Hosen1, Eduardo Nagore2 and Rajiv Kumar1,3

1Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

2Department of Dermatology, Instituto Valenciano de Oncologia, Valencia, Spain

3German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany

Correspondence to:

Rajiv Kumar, email: r.kumar@dkfz.de

Keywords: exome-sequencing, seborrheic keratosis, skin cancer, somatic mutations

Received: February 21, 2017    Accepted: March 19, 2017    Published: March 30, 2017

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.


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