Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors

Duperret, Elizabeth K.; Oh, Se H.; McNeal, Andrew S.; Prouty, Stephen M.; Ridky, Todd W.

doi:10.4161/cc.28492

Cited by 31 publications

(34 citation statements)

References 28 publications

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“…It has been suggested that a positive feedback loop between FGFR3 and the transcription factor FOXN1 stalls affected keratinocytes in a pro-differentiation mode and thereby prevents their malignant progression [11]. In our data we did find that high FGFR3 expressing seborrheic keratoses had high levels of FOXN1, but we did not observe increased FOXN1 expression due to activating FGFR3 mutations [11, 49]. While some earlier reports showed association of FGFR3 mutations with increased patient age, we observed statistically significantly increased frequency of mutations in patients below the median age.…”

Section: Discussioncontrasting

confidence: 50%

Genetic alterations in seborrheic keratoses

et al. 2017

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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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Section: Discussioncontrasting

confidence: 50%

Genetic alterations in seborrheic keratoses

et al. 2017

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“…Though, the contribution of FGFR3 protein overexpression to tumor progression seems to be tumortype dependent. FGFR3 protein overexpression drives tumor progression in bladder cancer, lung cancer, multiple myeloma, and glioblastoma, whereas it prevents tumor progression in cutaneous squamous cell carcinoma [25,26]. In HNSCC, FGFR3 protein overexpression seems to drive tumor progression, as reported by Uzawa et al [17].…”

Section: Quantitative Reverse Transcription Polymerase Chainmentioning

confidence: 87%

Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

et al. 2015

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Fibroblast growth factor receptor 3 (FGFR3) is a member of the fibroblast growth factor receptor tyrosine kinase family. It has been identified as a promising therapeutic target in multiple types of cancer. We have investigated FGFR3 protein expression and FGFR3 gene copy‐numbers in a single well‐documented cohort of oral and oropharyngeal squamous cell carcinoma. Tissue microarray sets containing 452 formalin‐fixed paraffin‐embedded tissues were immunohistochemically stained with an anti‐FGFR3 antibody and hybridized with a FGFR3 fluorescence in situ hybridization probe. FGFR3 protein expression was correlated with clinicopathological and survival data, which were retrieved from electronic medical records. FGFR3 mRNA data of 522 head and neck squamous cell carcinoma (HNSCC) were retrieved from The Cancer Genome Atlas (TCGA). Fibroblast growth factor receptor 3 (FGFR3) protein was overexpressed in 48% (89/185) of oral and 59% (124/211) of oropharyngeal squamous cell carcinoma. Overexpression of FGFR3 protein was not related to overall survival or disease‐free survival in oral (HR[hazard ratio]: 0.94; 95% CI: 0.64–1.39; P = 0.77, HR: 0.94; 95% CI: 0.65–1.36; P = 0.75) and oropharyngeal squamous cell carcinoma (HR: 1.21; 95% CI: 0.81–1.80; P = 0.36, HR: 0.42; 95% CI: 0.79–1.77; P = 0.42). FGFR3 mRNA was upregulated in 3% (18/522) of HNSCC from the TCGA. The FGFR3 gene was gained in 0.6% (1/179) of oral squamous cell carcinoma but no amplification was found in oral and oropharyngeal squamous cell carcinoma. In conclusion, FGFR3 protein is frequently overexpressed in oral and oropharyngeal squamous cell carcinoma. Therefore, it may serve as a potential therapeutic target for FGFR3‐directed therapies in oral and oropharyngeal squamous cell carcinoma.

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“…Primary human keratinocytes, melanocytes and fibroblasts were incorporated into the appropriate epidermal or stromal compartments of devitalized acellular human dermis and supported at the air-liquid interface, where tissue stratifies and differentiates into three-dimensional (3D) skin (Fig. 1A) (Duperret et al, 2014;Monteleon et al, 2015;Ridky et al, 2010).…”

Section: Integrin αV Is Required For Human Keratinocyte Proliferationmentioning

confidence: 99%

Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

Duperret

Dahal

Ridky

2015

Journal of Cell Science

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Integrins play crucial roles in epithelial adhesion, proliferation, wound healing and cancer. In the epidermis, the roles of many integrin subunits are incompletely defined and mechanistic details regarding their functions are lacking. We performed a multiplexed small hairpin (sh)RNA screen to define roles for each subunit in human organotypic skin. We show that integrin-αv (also known as ITGAV) heterodimers are essential for epidermal generation, with integrin-αv loss driving a keratinocyte G1-S cell cycle block. Surprisingly, integrin αv is not localized within keratinocyte focal adhesions, and instead maintains proliferation by controlling cellular (c)-Myc translation through FAK, p38β and p90RSK1. These phenotypes depend only on the binding partners of integrin-αv -integrin β5 and integrin β6 (also known as ITGB5 and ITGB6, respectively). Through inducible depletion of integrin αv in both normal organotypic epidermis and Ras-driven invasive neoplasia, we show that integrin αv is required for de novo tissue generation and neoplastic invasion but that it is dispensable for epidermal maintenance. Heterodimers of integrin αv with integrin β5 (integrin αvβ5) or integrin β6 (integrin αvβ6) are required to similar extents for neoplastic invasion, thus identifying integrin αvβ5 and integrin αvβ6 heterodimers as potential therapeutic targets for epidermal squamous cell carcinoma.

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Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors

Cited by 31 publications

References 28 publications

Genetic alterations in seborrheic keratoses

Genetic alterations in seborrheic keratoses

Fibroblast growth factor receptor 3 protein is overexpressed in oral and oropharyngeal squamous cell carcinoma

Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

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