What is the role of genetics in the pathophysiology of seborrheic keratosis?

Updated: Oct 14, 2020
  • Author: Arthur K Balin, MD, PhD, FACP; Chief Editor: William D James, MD  more...
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Answer

A high frequency of mutations in the gene encoding the tyrosine kinase receptor FGFR3 (fibroblast growth factor receptor 3) has been found in certain types of seborrheic keratoses. This was the first clue into the genetic basis for the pathogenesis of seborrheic keratoses. FGFR3 belongs to a class of transmembrane tyrosine kinase receptors involved in signal transduction to regulate cell growth, differentiation, and migration, as well as wound healing and angiogenesis. Upon ligand binding, FGFR3 dimerizes, which, in turn, induces phosphorylation of the kinase domain. Activating mutations in FGFR3 have been found in approximately 40% of hyperkeratotic seborrheic keratoses, 40% of acanthotic seborrheic keratoses, and 85% of adenoid seborrheic keratoses. [7, 8, 9]

More than 80% of seborrheic keratoses have at least one mutation, and 45% have more than one mutation in an oncogene such as FGFR3, PIK3CA, KRAS, and EGFR. [10] The most frequently mutated genes in seborrheic keratoses are FGFR3 (found in 71% or sporadic seborrheic keratosis) and the p110 catalytic subunit of phosphatidylinositol 3 kinase (PI3K) (found in 50% of sporadic seborrheic keratoses). [11] Seborrheic keratoses have a higher proliferative rate than normal keratinocytes, and apoptosis is suppressed in seborrheic keratoses compared with healthy skin. [12, 13] Both of these proteins effect the activity of Akt kinase. The activation of Akt kinase enhances the survival of cells by blocking the p53 pathway and the FOXO-mediated proapoptotic cascade. [14] Thus, the signaling kinase Akt is critical in preventing seborrheic keratosis cells from undergoing programmed cell death. When Akt is inhibited, seborrheic keratosis cells quickly die through apoptosis. [15]

Seborrheic keratoses have a varying degree of pigmentation. In pigmented seborrheic keratoses, the proliferating keratinocytes trigger the activation of neighboring melanocytes by secreting melanocyte-stimulating cytokines. Endothelin-1 has dual stimulatory effects on DNA synthesis and melanization of human melanocytes and has been implicated as playing a part in the hyperpigmentation observed in seborrheic keratoses. [16] Immunohistochemically, the keratinocytes of seborrheic keratoses express low molecular weight keratin but often exhibit a partial lack of the high molecular weight forms of keratin.


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