Genetic alterations in seborrheic keratoses

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.

Noninvasive Analysis of High-Risk Driver Mutations and Gene Expression Profiles in Primary Cutaneous Melanoma

“…In our study, invasive melanomas carried multiple hotspot mutations over twice as often as in situ melanomas; multiple mutations have also been reported to be associated with adverse histopathology (higher mitotic index and tumor thickness), disease progression, and worse prognosis by others (Nagore et al, 2016). Although TERT promoter mutations, among other mutations, have also been described in lesions other than melanoma (Heidenreich et al, 2017), they are independently associated with poor overall survival in patients with nonacral melanomas (median survival ¼ 80 months vs. 291 months for wild type, P ¼ 0.006), and the coexistence of TERT promoter and BRAF mutations in cutaneous melanoma is associated with clinicopathological features of tumor aggressiveness (Griewank et al, 2014;Macerola et al, 2015). Additionally, TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk for aggressive disease (Nagore et al, 2016).…”

A pigmented and eroded lesion on the buttock

“…1 C P D neoplasm within the benign precursor tumour could be supported by a common mutational profile between the two entities. Although mutations in the HRAS or EGFR genes have been reported in both neoplasms, 3,4 further knowledge of their genetics is needed to better understand this association. However, in our case, as in the case reported by Madan et al 2 the lesion presented as a solitary large tumour, and histopathological features of SK were found at both margins of the porocarcinoma.…”

Cells to Surgery Quiz: November 2018

“…Utilizing dermoscopy allows recognition of common SK features including milia-like cyst, comedo-like openings, and ridges forming a cerebriform pattern. The most common activating mutations implicated in seborrheic keratosis include fibroblast growth factor receptor 3 in 48% of lesions and phosphatidlyinositol-4,5-bisphosphate 3-kinase in 32% of seborrheic keratoses; both mutations lead to activation of the Akt pathway, which enhances cell survival by blocking p53 (Heidenreich et al, 2017). Common treatments for SK removal include cryotherapy, electrosurgery, and surgical excision.…”