Activation of fibroblast growth factor receptor 3 and oncogene-induced senescence in skin tumours

Hida, Yasutoshi; Kubo, Yoshiaki; Arase, Seiji

doi:10.1111/j.1365-2133.2009.09068.x

Cited by 18 publications

(23 citation statements)

References 28 publications

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“…Other genes mutated in seborrheic keratoses include HRAS , KRAS , EGFR and AKT1 [3, 6, 9]. Activation of FGFR3 appears to be a common feature in the lesions that can to some extent be attributed to FGFR3 mutations [8, 10]. 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].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

Genetic alterations in seborrheic keratoses

et al. 2017

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“…1 Although the tumors are hyperproliferative, they respect the underlying basement membrane, are well-differentiated, rarely exhibit cytological abnormalities that are common to squamous cell carcinomas (SCCs), and are thought to rarely progress to malignancy. 2,3 39-85% of clinical SK tumors harbor a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, depending on the histological sub-type and patient demographic. 2,[4][5][6][7] Most FGFR3 mutations in SKs, as well as malignant tumors in other organs, are localized to positions 248 or 249, where cysteine substitutions lead to increased FGFR3 dimer stability and constitutive receptor activation in the absence of ligand.…”

Section: Introductionmentioning

confidence: 99%

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

Duperret

McNeal

et al. 2014

Cell Cycle

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“…These results indicate that cumulative lifetime UV light exposure to skin and replicating errors in the DNA could be important factors in the pathogenesis of FGFR3 -mutated SK. The R248C mutation, a typical outcome of UV radiation exposure, is the most frequent mutation identified in SKs (19–50% of the reported FGFR3 mutations), further supporting this hypothesis of a UV light association [10,35,36,37,38,39]. …”

Section: Fgfr3 Mutations: Different Consequences Of Germline Versus Smentioning

confidence: 56%

“…Besides genetic disposition, sun exposure and infection have been implicated as etiological factors. Based on the present knowledge, 39–85% of SKs harbor FGFR3 mutations, suggesting that FGFR3 mutations may contribute to the development of SKs [10,35,36,37,38,39]. Up to six different FGFR3 mutations have been identified in different SKs from the same patient, and up to three simultaneous FGFR3 mutations have been found within the same SK [36].…”

Section: Fgfr3 Mutations: Different Consequences Of Germline Versus Smentioning

confidence: 99%

“…For a long time, FGFR3 mutations seemed to be restricted to benign tumorigenesis in the skin [38,51]. However, activating mutations in the FGFR3 gene were recently identified in actinic cheilitis (3/15; a precancerous lesion) and in one squamous cell carcinoma of the lower lip (1/5), suggesting that an oncogenic role of FGFR3 in the skin should not yet be ruled out [52].…”

Section: Fgfr3 Mutations: Different Consequences Of Germline Versus Smentioning

confidence: 99%

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<i>FGFR3</i> Mutations and the Skin: Report of a Patient with a <i>FGFR3</i> Gene Mutation, Acanthosis Nigricans, Hypochondroplasia and Hyperinsulinemia and Review of the Literature

Blomberg

Jeppesen²,

Skovby³

et al. 2010

Dermatology

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Fibroblast growth factor receptor 3 (FGFR3) gene mutations in the germline are well-known causes of skeletal syndromes. Somatic FGFR3 mutations have been found in malignant neoplasms and more recently in several cutaneous elements. We present a 14-year-old girl with mild hypochondroplasia who developed acanthosis nigricans. The report of a K650Q mutation in the FGFR3 gene in a similar case prompted us to conduct a point mutation analysis. The K650Q mutation was confirmed, but in contrast to the previous case, we additionally report findings of hyperinsulinemia. In the recent literature, an increasing number of different cutaneous elements have been found to harbor mutations of FGFR3, suggesting that FGFR3 plays a role in the pathogenesis of these elements. We review the present literature, describing studies in which FGFR3 mutations have been investigated in skin lesions: primarily seborrheic keratoses and epidermal nevi, but also other benign skin tumors and a single case of a squamous cell carcinoma. In addition, an overview of the FGFR3 point mutations in relation to each cutaneous element is given. Based on the current knowledge, it seems likely that these cutaneous lesions have a common genetic background. Our case shows that FGFR3 mutation analysis should be considered in case of the coexistence of acanthosis nigricans and a skeletal dysplasia. Testing for hyperinsulinemia is essential, also if a gene mutation is confirmed.

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Activation of fibroblast growth factor receptor 3 and oncogene-induced senescence in skin tumours

Cited by 18 publications

References 28 publications

Genetic alterations in seborrheic keratoses

Genetic alterations in seborrheic keratoses

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

<i>FGFR3</i> Mutations and the Skin: Report of a Patient with a <i>FGFR3</i> Gene Mutation, Acanthosis Nigricans, Hypochondroplasia and Hyperinsulinemia and Review of the Literature

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