Mosaicism of activatingFGFR3        mutations in human skin causes epidermal nevi

Hafner, Christian

doi:10.1172/jci28163

Cited by 203 publications

(150 citation statements)

References 57 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…42 It has been shown that a proportion of epidermal nevi result from activating embryonic mutations in FGFR3 and PI3K presenting with mosaicism in the skin. 32,43,44 In any event, similar to what has been reported for bladder and skin tumors, the association of FGFR3 alterations with prostate and skin tumors cannot be firmly established from the results of this study, and it deserves further research in larger series of patients, to elucidate the role of FGFR3 in the pathogenesis of different coexisting tumors. The cell type affected by the FGFR3 mutation as well as different involved cofactors and signaling pathways may contribute to the diverse tumoral phenotypes.…”

Section: Discussionmentioning

confidence: 44%

FGFR3 mutations in prostate cancer: association with low-grade tumors

et al. 2009

View full text Add to dashboard Cite

Prostate cancer is the second cause of cancer-related death in men of the Western World. The role of FGFR3 and its abnormalities in prostate cancer are not known. FGFR3 mutations have been reported in some human tumors. Few studies have analyzed the mutations of FGFR3 in prostate tumors, and no mutations have been previously reported. Prevalence of FGFR3 somatic mutations was investigated in a series of prostate tumors. The presence of other tumors in these patients, including urothelial, skin, colon, and lung neoplasms, was recorded. Mutational analysis of exons 7, 10, and 15 of FGFR3 revealed 9 mutations in the 112 prostate tumors studied (8%). Most of them consisted of the missense change S249C. The prevalence of mutations in tumors with combined Gleason score ¼ 6 is 18% (8/45) compared to 3% (1/36) for tumors with grade ¼ 7, and 0% (0/31) for those with grade Z8 and metastases (P ¼ 0.007). The frequency of FGFR3 mutations in autopsy and biopsy samples was 6 and 9%, respectively. The prevalence of FGFR3 mutations in prostate tumors from patients with only prostate cancer was 2% compared to 23% in prostate tumors from patients with other associated neoplasms (P ¼ 0.001). This is the first report of molecular changes of FGFR3 in prostate cancer. This gene does not seem to be central to the pathogenesis of prostate cancer, but it is significantly associated with a subgroup of low-grade prostate tumors, and with the finding of other tumors, mainly arising in bladder and skin.

show abstract

Section: Discussionmentioning

confidence: 44%

FGFR3 mutations in prostate cancer: association with low-grade tumors

et al. 2009

View full text Add to dashboard Cite

show abstract

“…5 Epidermal nevi, which are benign congenital skin lesions and histologically very similar to seborrheic keratoses, show also FGFR3 mutations as an underlying genetic basis. 8 Therefore, evidence is growing that FGFR3 mutations are important genetic alterations in the pathogenesis of benign acanthotic skin tumors. 10 However, not all seborrheic keratoses and epidermal nevi display FGFR3 mutations, suggesting the involvement of further genes.…”

Section: Discussionmentioning

confidence: 99%

“…5,6,11 Most of the FGFR3 mutations in human skin tumors as well as in urothelial carcinoma and in the germline of patients with skeletal dysplasia syndromes appear to be restricted to several hot spots in exons 7, 10, and 15. 5,6,8,[12][13][14] Interestingly, all FGFR3 mutations detected in human skin tumors so far are associated with thanatophoric dysplasia, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and Crouzon syndrome in germline. The FGFR3 mutations causing the above-mentioned skeletal dysplasia syndromes are associated with a strong constitutive receptor activation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization

et al. 2007

View full text Add to dashboard Cite

Somatic activating fibroblast growth factor 3 (FGFR3) mutations in human skin can cause seborrheic keratoses, one of the most frequent skin tumors in man. However, details of the involved mechanisms remain elusive. We analyzed 65 acanthotic seborrheic keratoses with varying vertical diameters for FGFR3 mutations using a SNaPshot s multiplex assay. Immunohistochemistry was performed for Ki-67, bcl-2 and FGFR3 protein in all seborrheic keratoses and 19 normal skin samples. FGFR3 mutations were detected in 37 of 65 seborrheic keratoses (57%). These mutations were found both in flat (initial) and thick seborrheic keratoses. FGFR3 mutations were significantly associated with increased age and localization on the head and neck (Po0.01). Ki-67 expression was significantly higher in seborrheic keratoses than in normal epidermis independent of the FGFR3 status (Po0.001). Furthermore, FGFR3 mutations were associated with an increased expression of bcl-2 and FGFR3 protein (Po0.05). Our results indicate that FGFR3 mutations can occur early in the pathogenesis of at least a subset of seborrheic keratoses. Increased age appears to be a risk factor for these mutations. Keywords: seborrheic keratosis; acanthosis; FGFR3 mutation; bcl-2; Ki-67 Seborrheic keratoses represent one of the most common skin tumors in man. Their prevalence increases with age. Seborrheic keratoses are detected in 80-100% of people over 50 years. 1,2 Affected individuals can show large numbers of lesions. Yeatman et al reported an average number of 69 seborrheic keratoses/person in people aged more than 75 years. Seborrheic keratoses are typically localized on the head, the trunk and the extremities with the exception of the palms and soles. They present as well-demarcated brownish plaques and later may show a verrucous surface. Their horizontal diameter ranges from a few millimeters to several centimeters. Three major histologic subtypes are known including acanthotic, hyperkeratotic and adenoid seborrheic keratoses variants. 3 Common histological features are acanthosis, papillomatosis and hyperkeratosis along with a varying degree of pigmentation. The vertical diameter (tumor thickness) of seborrheic keratoses varies considerably. Flat (initial) seborrheic keratoses frequently show gradual vertical growth within years. 3 However, malignant transformation is a very rare event in seborrheic keratoses, and the reported cases may also represent collision tumors of seborrheic keratoses and other epidermal malignancies such as basal cell carcinoma and squamous cell carcinoma. 4 Although seborrheic keratoses are very common tumors and represent one of the most disfiguring signs of skin aging, their pathogenesis is only marginally understood. Recently, activating FGFR3 mutations in the epidermis were shown to be involved in the development of seborrheic keratoses. 5 Transgenic mice expressing the S249C FGFR3 mutation in the basal layer of the epidermis under the control of the keratin 5 promoter developed thickening of the skin and verrucous skin tumors

show abstract

“…EN can present as single lesions, as multiple lesions, or in association with more complex phenotypes (2). Because of their anatomical distribution, it has long been proposed that EN arise as a result of mosaicism (3); a proportion of EN harbor somatic embryonic mutations in the gene coding for fibroblast growth factor receptor (FGFR3) and for the p110α subunit of phosphoinositide 3-kinase (PIK3CA) (4)(5)(6).…”

mentioning

confidence: 99%

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Hafner

Toll

Fernández-Casado

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Malignant tumors result from the accumulation of genetic alterations in oncogenes and tumor suppressor genes. Much less is known about the genetic changes in benign tumors. Seborrheic keratoses (SK) are very frequent benign human epidermal tumors without malignant potential. We performed a comprehensive mutational screen of genes in the FGFR3-RAS-MAPK and phosphoinositide 3-kinase (PI3K)-AKT pathways from 175 SK, including multiple lesions from each patient. SK commonly harbored multiple bona fide oncogenic mutations in FGFR3, PIK3CA, KRAS, HRAS, EGFR, and AKT1 oncogenes but not in tumor suppressor genes TSC1 and PTEN. Despite the occurrence of oncogenic mutations and the evidence for downstream ERK/MAPK and PI3K pathway signaling, we did not find induction of senescence or a DNA damage response. Array comparative genomic hybridization (aCGH) analysis revealed that SK are genetically stable. The pattern of oncogenic mutations and X chromosome inactivation departs significantly from randomness and indicates that spatially independent lesions from a given patient share a clonal relationship. Our findings show that multiple oncogenic mutations in the major signaling pathways involved in cancer are not sufficient to drive malignant tumor progression. Furthermore, our data provide clues on the origin and spread of oncogenic mutations in tissues, suggesting that apparently independent (multicentric) adult benign tumors may have a clonal origin.

show abstract

Mosaicism of activatingFGFR3 mutations in human skin causes epidermal nevi

Cited by 203 publications

References 57 publications

FGFR3 mutations in prostate cancer: association with low-grade tumors

FGFR3 mutations in prostate cancer: association with low-grade tumors

FGFR3 mutations in seborrheic keratoses are already present in flat lesions and associated with age and localization

Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors

Contact Info

Product

Resources

About