Clinical spectrum of fibroblast growth factor receptor mutations

Passos-Bueno, M.R.; Wilcox, W.R.; Jabs, Ethylin Wang; Sertié, A.L.; Alonso, Luís Garcia; Kitoh, H.

doi:10.1002/(sici)1098-1004(1999)14:2<115::aid-humu3>3.3.co;2-u

Cited by 90 publications

(110 citation statements)

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“…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%

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

et al. 2007

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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

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Section: Discussionmentioning

confidence: 99%

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

et al. 2007

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“…[13][14][15] The somatic mutations included the S252W and P235R changes, which are associated with the Apert syndrome, the N549K and K659M, which are associated with Crouzon syndrome, as well as the N550K change. 31 Interestingly, FGFR2 and K-RAS FGFR2 in endometrial cancer mutations were mutually exclusive events, whereas mutations in FGFR2 and PTEN frequently coexisted. Ectopic expression of one FGFR2 mutation (S252W) in NIH 3T3 cells conferred anchorage-independent growth, suggesting an oncogenic role for FGFR2 mutations.…”

Section: Fgfr2 Mutationsmentioning

confidence: 99%

FGFR2 alterations in endometrial carcinoma

et al. 2011

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Fibroblast growth factor receptor 2 (FGFR2) is a tyrosine kinase receptor involved in many biological processes such as embryogenesis, adult tissue homeostasis and cell proliferation. Mutations in FGFR2 have been reported in up to 10-12% of endometrial carcinomas identical to those found in congenital craniofacial disorders. Inhibition of FGFR2 could be a new therapeutic target in endometrial carcinoma. FGFR2 immunostaining was assessed in three tissue microarrays: one constructed from paraffin-embedded blocks of 60 samples of normal endometrium in different phases of menstrual cycle, and two tissue microarrays containing endometrial carcinoma samples (95 and 62 cases). FGFR2 expression was correlated with stage, histological type and grade as well as with immunostaining of PTEN, RASSF1A, estrogen and progesterone receptors, KI67, Cyclin D1, STAT-3 and SPRY2. FGFR2 mutations were assessed by PCR and direct sequencing, with DNA obtained from 31 paraffin-embedded endometrial carcinoma samples. In normal endometrium, FGFR2 expression was higher in the secretory than in the proliferative phase (P ¼ 0.001), with an inverse correlation with Ki67 (P ¼ 0.00032), suggesting a tumor-suppressor role for FGFR2 in normal endometrium. Cytoplasmic expression of FGFR2 was higher in endometrial carcinoma when compared with the atrophic endometrium from the same patients (P ¼ 0.0283), but was lower in comparison with normal endometrium from women in the menstrual cycle. Interestingly, nuclear staining was observed in some cases, and it was less frequent in endometrial carcinoma when compared with the adjacent atrophic endometrium (P ¼ 0.0465). There were no statistical differences when comparing superficial and myoinvasive endometrial carcinoma samples. Endometrioid endometrial carcinomas showed higher expression of FGFR2 than nonendometrioid endometrial carcinomas (fold change 2.56; P ¼ 0.0015). Grade III endometrioid endometrial carcinomas showed decreased FGFR2 expression when compared with grade II endometrioid endometrial carcinomas (P ¼ 0.0055). No differences were found regarding pathological stage. Two missense mutations of FGFR2 gene were detected in exons 6 and 11 (S252W and N549K, respectively; 6.45%). Results support the hypothesis that FGFR2 has a dual role in the endometrium, by inhibiting cell proliferation in normal endometrium during the menstrual cycle, but acting as an oncogene in endometrial carcinoma.

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“…Also, there is clear redundancy between Fgfr1 and Fgfr2 in kidney mesenchyme. In humans, activating and loss of function mutations in FGFRs cause syndromes that are sometimes associated with urogenital anomalies [2][3][4][5][6][7]. Perturbations in fibroblast growth factor receptor signaling may also be responsible for sporadic cases of human renal congenital malformations and VUR.…”

Section: Resultsmentioning

confidence: 99%

“…Although the underlying genetic defects leading to structural kidney disease are largely unknown, there are syndromes in which mutations in fibroblast growth factor receptors (FGFRs) lead to renal anomalies. For example activating mutations of FGFR1 and/or 2 cause syndromes such as Apert's syndrome, Antley-Bixler syndrome, Pfeiffer syndrome, and Beare-Stevenson syndrome, which are sometimes associated with urogenital anomalies such as hydroureter, solitary kidney, and VUR [2][3][4][5]. Loss of function mutations in FGFR1 have also been associated with some variants of Kallman syndrome that can be associated with unilateral renal aplasia.…”

Section: Introductionmentioning

confidence: 99%

Role of fibroblast growth factor receptor signaling in kidney development

Bates

2007

Pediatr Nephrol

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Fibroblast growth factor receptors (Fgfrs) are expressed throughout the developing kidney. Several early studies have shown that exogenous fibroblast growth factors (Fgfs) affect growth and maturation of the metanephric mesenchyme (MM) and ureteric bud (UB). Transgenic mice that overexpress a dominant negative receptor isoform develop renal aplasia/severe dysplasia, confirming the importance of Fgfrs in renal development. Furthermore, global deletion of Fgf7, Fgf10, and Fgfr2IIIb (isoform that binds Fgf7 and Fgf10) in mice leads to small kidneys with fewer collecting ducts and nephrons. Deletion of Fgfrl1, a receptor lacking intracellular signaling domains, causes severe renal dysgenesis. Conditional targeting of Fgf8 from the MM interrupts nephron formation. Deletion of Fgfr2 from the UB results in severe ureteric branching and stromal mesenchymal defects, although loss of Frs2α (major signaling adapter for Fgfrs) in the UB causes only mild renal hypoplasia. Deletion of both Fgfr1 and Fgfr2 in the MM results in renal aplasia with defects in MM formation and initial UB elongation and branching. Loss of Fgfr2 in the MM leads to many renal and urinary tract anomalies as well as vesicoureteral reflux. Thus, Fgfr signaling is critical for patterning of virtually all renal lineages at early and later stages of development.

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Clinical spectrum of fibroblast growth factor receptor mutations

Cited by 90 publications

References 0 publications

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

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

FGFR2 alterations in endometrial carcinoma

Role of fibroblast growth factor receptor signaling in kidney development

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