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Current research highlighted the importance to recognize feasible biomarkers for early diagnoses and treatment in oral cancer. Our study analyzed the expression and spatial distribution of ALDH1A1, FGFR2, caspase-3, and CD44 in Oral Squamous Cell Carcinoma (OSCC) and leukoplakia with and without oral mucosal dysplasia. Paraffin-embedded samples of OSCC (n=5), leukoplakia with (n=5) and without (n=5) dysplasia obtained by incisional biopsies were processed using conventional histochemical techniques. Immunohistochemistry was performed using antibodies against ALDH1A1, FGFR2, caspase-3, and CD44. Images of the immunohistochemically stained tissue sections were analyzed according to the intensity of the immunostaining of each marker and classified in Scores. The Kruskal-Wallis test was performed (p≤0.05). Our results demonstrated a statically difference in the expression of all immunomarkers between OSCC and leukoplakia without dysplasia, being more significant in FGFR2 and ALDH1A1. Within the limitations of this study, our data showed that all biomarkers were overexpressed in OSCC and leukoplakia with oral mucosa dysplasia, suggesting that the presence of dysplasia is a significant clinic-pathologic predictor for malignant transformation., La actual evidencia científica enfatiza la importancia de reconocer biomarcadores viables para el diagnóstico y tratamiento temprano del cáncer oral. Nuestro estudio piloto analizó la expresión y distribución espacial de ALDH1A1, FGFR2, caspasa-3 y CD44 en carcinoma oral de células escamosas (COCE) y en leucoplasia con o sin displasia de la mucosa oral. Las muestras incluidas en parafina de COCE (n=5), con (n=5) y sin (n=5) displasia fueron obtenidas mediante biopsias incisionales, las cuales se procesaron utilizando técnicas histoquímicas convencionales. El análisis inmunohistoquímico se realizó utilizando anticuerpos contra ALDH1A1, FGFR2, caspasa-3 y CD44. Las imágenes de las secciones de cada muestra fueron analizadas según la intensidad de inmunoexpresión de cada marcador y se clasificaron en diferentes escalas (scores). Se realizó la prueba de Kruskal-Wallis (valores de p<0,05). Nuestros resultados demostraron una diferencia estadística en la expresión de todos los inmunomarcadores entre COCE y las muestras con leucoplasia sin displasia, siendo más significativa en FGFR2 y ALDH1A1. Considerando las limitaciones de este estudio, los datos sugieren que la presencia de displasia en la mucosa oral es un importante predictor clínico-patológico de transformación maligna.

Simple Summary: Heritable rare high- and moderate-risk mutations in breast cancer susceptibility genes are known of, alongside 170 common genetic low risk variants with a minor increase in risk. However, based on genetic studies, we know that over half of the breast cancer heritability is still unexplained. By analyzing combinations of chromosomal nearby variants, so-called haplotypes, and their association to breast cancer we could identify a novel genetic breast cancer risk locus on chromosome 8 and confirm three well known low risk loci on Chr 10, 11 and 16. (1) Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2) Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4) Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population., De två första författarna delar förstaförfattarskapet.

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population., De två första författarna delar förstaförfattarskapet.

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population., De två första författarna delar förstaförfattarskapet.

Carpal tunnel syndrome (CTS) and Dupuytren's disease (DD) are fibrotic conditions that affect the connective tissue of the hand and limit its functionality. The exact molecular mechanism underlying the fibrosis is unknown, and only some profibrotic factors have been investigated. In this cross-sectional study, we analyzed the expression of FGF signaling pathway molecules associated with fibrotic changes in the palmar fascia and the flexor retinaculum of 15 CTS patients and both clinically affected and unaffected palmar fascia of 15 DD patients, using immunofluorescence techniques. The expression of FGFR1, FGFR2, and CTGF in the blood vessel walls and surrounding connective tissue cells differed significantly between the analyzed groups, with changes in expression present even in clinically unremarkable tissues from DD patients. We also found altered expression of the analyzed factors, as well as TGF-beta 1 and syndecan-1 in DD-associated sweat glands, possibly implicating their role in the pathophysiology of the disease. The increased expression of profibrotic factors in the clinically unaffected palmar fascia of DD patients may indicate that more extensive excision is needed during surgical treatment, while the profibrotic factors could be potential targets for developing pharmacological therapeutic strategies against DD-associated fibrosis.

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population., De två första författarna delar förstaförfattarskapet.

Craniosynostosis are a heterogeneous group of genetic conditions characterized by the premature fusion of the skull bones. The most common forms of craniosynostosis are Crouzon, Apert and Pfeiffer syndromes. They differ from each other in various additional clinical manifestations, e.g., syndactyly is typical of Apert and rare in Pfeiffer syndrome. Their inheritance is autosomal dominant with incomplete penetrance and one of the main genes responsible for these syndromes is FGFR2, mapped on chromosome 10, encoding fibroblast growth factor receptor 2. We report an FGFR2 gene variant in a mother and daughter who present with different clinical features of Crouzon syndrome. The daughter is more severely affected than her mother, as also verified by a careful study of the face and oral cavity. The c.1032G>A transition in exon 8, already reported as a synonymous p.Ala344 = variant in Crouzon patients, also activates a new donor splice site leading to the loss of 51 nucleotides and the in-frame removal of 17 amino acids. We observed lower FGFR2 transcriptional and translational levels in the daughter compared to the mother and healthy controls. A preliminary functional assay and a molecular modeling added further details to explain the discordant phenotype of the two patients.

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population., De två första författarna delar förstaförfattarskapet.

A maytansin derivative, DM1, is a promising therapeutic compound for treating tumors, but is also a highly poisonous substance with various side effects. For clinical expansion, we tried to develop novel peptide-drug conjugates (PDCs) with DM1. In the study, a one-bead one-compound (OBOC) platform was used to screen and identify a novel, highly stable, non-natural amino acid peptide targeting the tyrosine receptor FGFR2. Then, the identified peptide, named LLC2B, was conjugated with the cytotoxin DM1. Our results show that LLC2B has high affinity for the FGFR2 protein according to an isothermal titration calorimetry (ITC) test. LLC2B-Cy5.5 binding to FGFR2-positive cancer cells was confirmed by fluorescent microscopic imaging and flow cytometry in vitro. Using xenografted nude mouse models established with breast cancer MCF-7 cells and esophageal squamous cell carcinoma KYSE180 cells, respectively, LLC2B-Cy5.5 was observed to specifically target tumor tissues 24 h after tail vein injection. Incubation assays, both in aqueous solution at room temperature and in human plasma at 37 °C, suggested that LLC2B has high stability and strong anti-proteolytic ability. Then, we used two different linkers, one of molecular disulfide bonds and another of a maleimide group, to couple LLC2B to the toxin DM1. The novel peptide-drug conjugates (PDCs) inhibited tumor growth and significantly increased the maximum tolerated dose of DM1 in xenografted mice. In brief, our results suggest that LLC2B-DM1 can be developed into a potential PDC for tumor treatment in the future.

研究グループは、血液2mlを用いて、fibroblast growth factor receptor 2 (FGFR2:線維芽細胞増殖因子受容体2型)を発現する癌細胞同定に成功しました。スキルス胃癌や胆管癌など難治癌の増殖進展にFGFR2遺伝子異常が関与していること が明らかになっており、FGFRシグナルを治療標的とした分子標的阻害剤の臨床試験が進行中です。同研究グループは、スキルス胃癌細胞がFGFR2タンパクを高発現していることを明らかにしてきたことを生かして、今回、胃癌患者100名の血液を用いて、血液中のFGFR2陽性癌細胞の検出が可能であること、また検出した癌細胞数と切除胃癌組織FGFR2発現や生存率との間に相関があることを明らかにしました。現在、癌遺伝子パネル検査を含め、分子標的薬の適応が摘出された癌組織を検査して判断されていますが、この方法では検査した癌組織が患者に現存する癌ではないため分子標的薬の適応判断が適切でない可能性があります。一方、今回の方法は患者血液中の癌細胞をリアルタイムに調べることでより正確な治療薬の判断が可能と考えられます。, Fibroblast growth factor receptor (FGFR) is associated with proliferation, migration, and angiogenesis of carcinomas, and FGFR signaling inhibitors are considered a key drug for the treatment of solid tumors with FGFR overexpression. Amplification of FGFR2 is reportedly identified in 3%-10% of gastric cancers (GCs). The aim of this study is to clarify whether the identification of the circulating tumor cells (CTCs) with FGFR2 overexpression is useful to detect patients with FGFR2-overexpressing GC....

Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.

Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.

This project investigated the role of FGFR2 isoforms (FGFR2b/FGFR2c) and their cognate FGF ligands in endometrial cancer development, prognosis, and treatment response via designing and validating an innovative BaseScope RNA in-situ hybridization assay and generating patient tumour-derived organoids. FGFR2c and high FGF18 expression were significantly associated with aggressive tumour characteristics and poor survival outcome. It was also noted FGFR2c expression is associated with progestin treatment failure in atypical hyperplasia and well-differentiated endometrial cancers. Overall, FGFR2c and FGF18 are independent prognostic biomarkers that could improve our ability to predict patient prognosis and predict response to FGFR inhibitor treatment in endometrial cancer.

Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.

Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.

Purpose Activating FGFR2 mutations have been identified in ~ 10% of endometrioid endometrial cancers (ECs). We have previously reported that mutations in FGFR2 are associated with shorter disease free survival (DFS) in stage I/II EC patients. Here we sought to validate the prognostic importance of FGFR2 mutations in a large, multi-institutional patient cohort. Methods Tumors were collected as part of the GOG 210 clinical trial “Molecular Staging of Endometrial Cancer” where samples underwent rigorous pathological review and had more than three years of detailed clinical follow-up. DNA was extracted and four exons encompassing the FGFR2 mutation hotspots were amplified and sequenced. Results Mutations were identified in 144 of the 973 endometrioid ECs, of which 125 were classified as known activating mutations and were included in the statistical analyses. Consistent with FGFR2 having an association with more aggressive disease, FGFR2 mutations were more common in patients initially diagnosed with stage III/IV EC (29/170;17%) versus stage I/II EC (96/803; 12%; p = 0.07, Chi-square test). Additionally, incidence of progression (progressed, recurred or died from disease) was significantly more prevalent (32/125, 26%) among patients with FGFR2 mutation versus wild type (120/848, 14%; p < 0.001, Fishers exact test). Using Cox regression analysis adjusting for known prognostic factors, patients with FGFR2 mutation had significantly (p < 0.025) shorter progression-free survival (PFS; HR 1.903; 95% CI 1.177–3.076) and endometrial cancer specific survival (ECS; HR 2.013; 95% CI 1.096–3.696). Conclusion In summary, our findings suggest that clinical trials testing the efficacy of FGFR inhibitors in the adjuvant setting to prevent recurrence and death are warranted.

Apert syndrome also called acrocephalosyndactyly Type I is characterized by craniosynostosis , symmetric syndactyly in all four limbs , mental retardation , skin and maxillofacial disorders ; It is caused by a mutation in the gene receptor 2 fibrobroblástico growth factor expressing FGFR2 autosomal dominant (AD ) . Case report: as is the acrocephaly and syndactyly in the hands and feet of newborn male case, Capurro of 38 weeks approximately, with classical phenotypic characteristics of this syndrome is presented as is the acrocephaly and syndactyly in hands and feet

A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon–Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon–Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes.

A major concern in FGFR2 craniofaciosynostosis is oculo-orbital disproportion, such that orbital malformation provides poor accommodation and support for the orbital contents and peri-orbita, leading to insufficient eyelid closure, corneal exposure and eventually to functional visual impairment. Fronto-facial monobloc osteotomy followed by distraction osteogenesis aims to correct midfacial growth deficiencies in Crouzon–Pfeiffer syndrome patients. Fronto-facial bipartition osteotomy followed by distraction is a procedure of choice in Apert syndrome patients. These procedures modify the shape and volume of the orbit and tend to correct oculo-orbital disproportion. Little is known about the detailed 3D shape of the orbital phenotype in CPS and AS, and about how this is modified by fronto-facial surgery. Twenty-eight patients with CMS, 13 patients with AS and 40 control patients were included. CT scans were performed before and after fronto-facial surgery. Late post-operative scans were available for the Crouzon–Pfeiffer syndrome group. Orbital morphology was investigated using conventional three-dimensional cephalometry and shape analysis after mesh-based segmentation of the orbital contents. We characterized the 3D morphology of CPS and AS orbits and showed how orbital shape is modified by surgery. We showed that monobloc-distraction in CPS and bipartition-distraction in AS specifically address the morphological characteristics of the two syndromes. © 2016 European Association for Cranio-Maxillo-Facial Surgery

Bent Bone Dysplasia-FGFR2 type is a relatively recently described bent bone phenotype with diagnostic clinical, radiographic, and molecular characteristics. Here we report on 11 individuals, including the original four patients plus seven new individuals with three longer-term survivors. The prenatal phenotype included stillbirth, bending of the femora, and a high incidence of polyhydramnios, prematurity, and perinatal death in three of 11 patients in the series. The survivors presented with characteristic radiographic findings that were observed among those with lethality, including bent bones, distinctive (moustache-shaped) small clavicles, angel-shaped metacarpals and phalanges, poor mineralization of the calvarium, and craniosynostosis. Craniofacial abnormalities, hirsutism, hepatic abnormalities, and genitourinary abnormalities were noted as well. Longer-term survivors all needed ventilator support. Heterozygosity for mutations in the gene that encodes Fibroblast Growth Factor Receptor 2 (FGFR2) was identified in the nine individuals with available DNA. Description of these patients expands the prenatal and postnatal findings of Bent Bone Dysplasia-FGFR2 type and adds to the phenotypic spectrum among all FGFR2 disorders. © 2016 Wiley Periodicals, Inc.

The transcription factor Nurr1 is expressed in the mouse olfactory bulb (OB), although it remains unknown whether it influences the generation of dopaminergic neurons (DA) (DA neurons) in cells isolated from this brain region. We found that expressing Nurr1 in proliferating olfactory bulb stem cells (OBSCs) produces a marked inhibition of cell proliferation and the generation of immature neurons immunoreactive for tyrosine hydroxylase (TH) concomitant with marked upregulations of Th, Dat, Gad, and Fgfr2 transcripts. In long‐term cultures, these cells develop neurochemical and synaptic markers of mature‐like mesencephalic DA neurons, expressing GIRK2, VMAT2, DAT, calretinin, calbindin, synapsin‐I, and SV2. Concurring with the increase in both Th and Gad expression, a subpopulation of induced cells was both TH‐ and GAD‐immunoreactive indicating that they are dopaminergic‐GABAergic neurons. Indeed, these cells could mature to express VGAT, suggesting they can uptake and store GABA in vesicles. Remarkably, the dopamine D1 receptor agonist SKF‐38393 induced c‐Fos in TH+ cells and dopamine release was detected in these cultures under basal and KCl‐evoked conditions. By contrast, cotransducing the Neurogenin2 and Nurr1 transcription factors produced a significant decrease in the number of TH‐positive neurons. Our results indicate that Nurr1 overexpression in OBSCs induces the formation of two populations of mature dopaminergic neurons with features of the ventral mesencephalon or of the OB, capable of responding to functional dopaminergic stimuli and of releasing dopamine. They also suggest that the accumulation of Fgfr2 by Nurr1 in OBSCs may be involved in the generation of DA neurons.

Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2.Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis.Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations.

Background. Apert Syndrome (AS) is one of the most severe syndromic craniosynostosis affecting neuro and viscerocranium and presenting with multisystemic anomalies altering physical aspects (general looks and short stature), sensorineural aspects (deafness and visual problems), cognitive development (mental retardation or trouble learning) and work inclusion (severe syndactyly in hands and feet). Its aetiology relies on mutation of the Fibroblast Growth Factor Receptor type 2 (FGFR2) gene, inherited by an autosomal dominant path.Materials and methods. 11 patients with suspicion of AS were clinically evaluated and molecularly tested for mutations in FGFR2 by RFLP.Results. Patients with AS from 0 to 32 years old were analized for mutations in FGFR2 gene. All of them had the classical phenotype of the disease. 63.6% of the patients had the S252W mutation while 36.4% had the P253R mutation.Discussion. Of all patients enrolled in this study it is notwworthy that some of them had short stature, while others had mental retardation or global development delay. Mutational frequencies for S252W and P253R did not show difference according to what has been reported worldwide. Although there is no data about the incidence of this disease locally, this study could be a first approach to its epidemiology in Colombia., Antecedentes. El síndrome de Apert (SA) es una de las craneosinostosis sindrómicas más severas que afecta el neuro y viscerocraneo y además presenta alteraciones multisistémicas con repercusiones en aspectos físicos (aspecto general y talla baja), sensoriales (hipoacusia y trastornos visuales), cognoscitivos (retardo mental o trastornos del aprendizaje) y de inclusión laboral (sindactilia severa en manos y pies). Su etiología es la mutación del receptor 2 del factor de crecimiento fibroblástico (FGFR2) y se hereda de forma autosómica dominante.Materiales y métodos. Se analizaron clínica y molecularmente 11 pacientes con sospecha de SA. Se realizó estudio mutacional mediante RFLP para el gen FGFR2.Resultados. Se confirmaron molecularmente los 11 pacientes con SA, cuyas edades oscilaron desde los 0 a 32 años. Todos los pacientes presentaron el fenotipo clásico. Se encontró un 63.6% de pacientes con la mutación S252W y 36.4% con P253R.Discusión. De los pacientes analizados, llamo la atención la presencia de talla baja y RM/RGD en algunos de ellos. Desde el punto de vista genotípico, las frecuencias mutacionales para S252W y P253R no mostraron diferencias con relación a lo reportado mundialmente. Aunque no se disponen de datos de la incidencia de esta patología a nivel local, este estudio podría ser el primer acercamiento para fines epidemiológicos en Colombia.

Background. Apert Syndrome (AS) is one of the most severe syndromic craniosynostosis affecting neuro and viscerocranium and presenting with multisystemic anomalies altering physical aspects (general looks and short stature), sensorineural aspects (deafness and visual problems), cognitive development (mental retardation or trouble learning) and work inclusion (severe syndactyly in hands and feet). Its aetiology relies on mutation of the Fibroblast Growth Factor Receptor type 2 (FGFR2) gene, inherited by an autosomal dominant path.Materials and methods. 11 patients with suspicion of AS were clinically evaluated and molecularly tested for mutations in FGFR2 by RFLP.Results. Patients with AS from 0 to 32 years old were analized for mutations in FGFR2 gene. All of them had the classical phenotype of the disease. 63.6% of the patients had the S252W mutation while 36.4% had the P253R mutation.Discussion. Of all patients enrolled in this study it is notwworthy that some of them had short stature, while others had mental retardation or global development delay. Mutational frequencies for S252W and P253R did not show difference according to what has been reported worldwide. Although there is no data about the incidence of this disease locally, this study could be a first approach to its epidemiology in Colombia., Antecedentes. El síndrome de Apert (SA) es una de las craneosinostosis sindrómicas más severas que afecta el neuro y viscerocraneo y además presenta alteraciones multisistémicas con repercusiones en aspectos físicos (aspecto general y talla baja), sensoriales (hipoacusia y trastornos visuales), cognoscitivos (retardo mental o trastornos del aprendizaje) y de inclusión laboral (sindactilia severa en manos y pies). Su etiología es la mutación del receptor 2 del factor de crecimiento fibroblástico (FGFR2) y se hereda de forma autosómica dominante.Materiales y métodos. Se analizaron clínica y molecularmente 11 pacientes con sospecha de SA. Se realizó estudio mutacional mediante RFLP para el gen FGFR2.Resultados. Se confirmaron molecularmente los 11 pacientes con SA, cuyas edades oscilaron desde los 0 a 32 años. Todos los pacientes presentaron el fenotipo clásico. Se encontró un 63.6% de pacientes con la mutación S252W y 36.4% con P253R.Discusión. De los pacientes analizados, llamo la atención la presencia de talla baja y RM/RGD en algunos de ellos. Desde el punto de vista genotípico, las frecuencias mutacionales para S252W y P253R no mostraron diferencias con relación a lo reportado mundialmente. Aunque no se disponen de datos de la incidencia de esta patología a nivel local, este estudio podría ser el primer acercamiento para fines epidemiológicos en Colombia.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

In this issue of Cancer Discovery, Guagnano and colleagues use a large and diverse annotated collection of cancer cell lines, the Cancer Cell Line Encyclopedia, to correlate whole-genome expression and genomic alteration datasets with cell line sensitivity data to the novel pan-fibroblast growth factor receptor (FGFR) inhibitor NVP-BGJ398. Their findings underscore not only the preclinical use of such cell line panels in identifying predictive biomarkers, but also the emergence of the FGFRs as valid therapeutic targets, across an increasingly broad range of malignancies.

Mutations in multiple oncogenes including KRAS, CTNNB1, PIK3CA and FGFR2 have been identified in endometrial cancer. The aim of this study was to provide insight into the clinicopathological features associated with patterns of mutation in these genes, a necessary step in planning targeted therapies for endometrial cancer. 466 endometrioid endometrial tumors were tested for mutations in FGFR2, KRAS, CTNNB1, and PIK3CA. The relationships between mutation status, tumor microsatellite instability (MSI) and clinicopathological features including overall survival (OS) and disease-free survival (DFS) were evaluated using Kaplan-Meier survival analysis and Cox proportional hazard models. Mutations were identified in FGFR2 (48/466); KRAS (87/464); CTNNB1 (88/454) and PIK3CA (104/464). KRAS and FGFR2 mutations were significantly more common, and CTNNB1 mutations less common, in MSI positive tumors. KRAS and FGFR2 occurred in a near mutually exclusive pattern (p = 0.05) and, surprisingly, mutations in KRAS and CTNNB1 also occurred in a near mutually exclusive pattern (p = 0.0002). Multivariate analysis revealed that mutation in KRAS and FGFR2 showed a trend (p = 0.06) towards longer and shorter DFS, respectively. In the 386 patients with early stage disease (stage I and II), FGFR2 mutation was significantly associated with shorter DFS (HR = 3.24; 95% confidence interval, CI, 1.35-7.77; p = 0.008) and OS (HR = 2.00; 95% CI 1.09-3.65; p = 0.025) and KRAS was associated with longer DFS (HR = 0.23; 95% CI 0.05-0.97; p = 0.045). In conclusion, although KRAS and FGFR2 mutations share similar activation of the MAPK pathway, our data suggest very different roles in tumor biology. This has implications for the implementation of anti-FGFR or anti-MEK biologic therapies.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

English: The aim of the study was to elucidate the variation in phenotypic expression observed within BRCA2 c.8162delG mutation positive families. The study attempted to identify possible genetic factors that contribute to the residual risk conferred by the BRCA2 founder mutation. As BC is a polygenetic disorder, polymorphisms within various low penetrance genes may contribute to the expression of the disease. The selection of the SNPs were based on the results of the CIMBA consortium and have been proven to be associated with an increased BC risk in the general population (Easton et al., 2007) and in BRCA2 mutation carriers specifically (Antoniou et al., 2008). Two SNPs (rs2234693 [PvuII] and rs9340799 [XbaI]) present within ESR1 as well as SNPs present in TNRC9 (rs3803662), LSP1 (rs3817198), MAP3K1 (rs889312) and FGFR2 (rs2981582) identified by GWAS have been implicated in BC risk. These six polymorphisms have been selected to evaluate the risk within the Afrikaner BRCA2 8162delG (c.7934del, p.Arg2645AsnfsX3) mutation carriers specifically. Genotyping of rs2234693 (PvuII) and rs9340799 (XbaI) was done by PCR-RFLP analysis whereas Taqman® assays were used for genotyping rs3803662 (TNRC9), rs3817198 (LSP1), rs889312 (MAP3K1) and rs2981582 (FGFR2). Automated allelic discrimination using the BioRad CFX Manager v1.1.308.1111 software were compared to manual discrimination methods to ensure robust genotyping. Cohen’s kappa analysis suggested a combination of automated (Method 1) and manual (Method 3) genotyping was best suited for accurate allelic discrimination except for LSP1. Due to an putative SNP detected within LSP1, the validity of the LSP1 results should be treated cautiously as no information on the frequency of the second putative SNP in white European individuals is available. Of the six polymorphisms analyzed, only rs2234693 (PvuII), indicated a possible association with BC (P-value = 0.0896), which should be explored within a larger study group. For FGFR2, Afrikaans: Die doel van hierdie studie was om die variasie waargeneem in die fenotipiese uitdrukking onder BRCA2 k.8162delG mutasie positiewe families toe te lig. Die studie het gepoog om verskeie genetiese faktore wat moontlik kan bydra tot die gesamentlike risiko wat toegeken word deur die BRCA2 stigtersmutasie, te identifiseer. Aangesien borskanker ʼn poligeniese siekte is, kan polimorfismes binne verskeie lae-penetrasie gene tot die uitdrukking van die siekte bydra. Die seleksie van die polimorfismes was gebaseer op die resultate van die CIMBA konsortium wat bewys het dat diè polimorfismes met verhoogde borskanker risiko in die algemene populasie (Easton et al., 2007) sowel as in die BRCA2 stigtersmutasie draers spesifiek geassosieerd is (Antoniou et al., 2008). Twee polimorfismes (rs2234693 [PvuII] en rs9340799 [XbaI]) teenwoordig in ESR1 asook die polimorfismes teenwoordig in TNRC9 (rs3803662), LSP1 (rs3817198), MAP3K1 (rs889312) en FGFR2 (rs2981582) wat deur GWAS geidentifiseer is, word met ‘n verhoogde borskanker risiko geassosieer. Die ses polimorfismes is gekies om die addisionele risiko in die Afrikaner BRCA2 k. 8162delG (k.7934del, p.Arg2645AsnfsX3) mutasie draers spesifiek te ondersoek. Genotipering van rs2234693 (PvuII) en rs9340799 (XbaI) is uitgevoer met behulp van ensiem snydings (RFLP), terwyl Taqman® analises gebruik is om rs3803662 (TNRC9), rs3817198 (LSP1), rs889312 (MAP3K1) en rs2981582 (FGFR2) te genotipeer. Outomatiese alleliese diskriminasie gedoen deur die BioRad CFX Manager v1.1.308.1111 sagteware is vergelyk met semi- en nie-outomatiese diskriminasie metodes om sodoende robuuste genotipering te verseker. Cohen se kappa analises het die datastelle vergelyk en aangedui dat die metode van analise van Metode 1 en Metode 3 die meeste ooreenstem, met LSP1 as die uitsondering. Die teenwoordigheid van ‘n addisionele polimorfisme binne dieselfde gebied, impliseer dat die data ingewin vir LSP1 met versigtigheid geïnterpreteer moet word. Geen inligti, National Health Laboratory Services (NHLS)

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecologic malignancies in the Western world. Fibroblast growth factor receptor (FGFR) signaling has been implicated to play a role in ovarian tumorigenesis. Mutational activation of one member of this receptor family, FGFR2, is a frequent event in endometrioid endometrial cancer. Given the similarities in the histologic and molecular genetics of ovarian and endometrial cancers, we hypothesized that activating FGFR2 mutations may occur in a subset of endometrioid ovarian tumors, and possibly other histotypes. METHODS: Six FGFR2 exons were sequenced in 120 primary ovarian tumors representing the major histologic subtypes. RESULTS: FGFR2 mutation was detected at low frequency in endometrioid (1/46, 2.2%) and serous (1/41, 2.4%) ovarian cancer. No mutations were detected in clear cell, mucinous, or mixed histology tumors or in the ovarian cancer cell lines tested. Functional characterization of the FGFR2 mutations confirmed that the mutations detected in ovarian cancer result in receptor activation. CONCLUSIONS: Despite the low incidence of FGFR2 mutations in ovarian cancer, the two FGFR2 mutations identified in ovarian tumors (S252W, Y376C) overlap with the oncogenic mutations previously identified in endometrial tumors, suggesting activated FGFR2 may contribute to ovarian cancer pathogenesis in a small subset of ovarian tumors.

Saethre-Chotzen syndrome is one of the most common craniosynostosis syndromes. It is an autosomal dominantly inherited disorder with variable expression that is caused by germline mutations in the TWIST1 gene or more rarely in the FGFR2 or FGFR3 genes. We have previously reported that patients with Saethre-Chotzen syndrome have an increased risk of developing breast cancer. Here we have analysed a cohort of 26 women with BRCA1/2-negative hereditary breast cancer to study whether a proportion of these families might have mutations in Saethre-Chotzen-associated genes. DNA sequence analysis of TWIST1 showed no pathogenic mutations in the coding sequence in any of the 26 patients. MLPA (multiplex ligation-dependent probe amplification)-analysis also showed no alterations in copy numbers in any of the craniofacial disorder genes MSX2, ALX4, RUNX2, EFNB1, TWIST1, FGFR1, FGFR2,FGFR3, or FGFR4. Taken together, our findings indicate that mutations in Saethre-Chotzen-associated genes are uncommon or absent in BRCA1/2-negative patients with hereditary breast cancer.

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.

Endometrial carcinoma is the most common gynecological malignancy in the United States. Although most women present with early disease confined to the uterus, the majority of persistent or recurrent tumors are refractory to current chemotherapies. We have identified a total of 11 different FGFR2 mutations in 3/10 (30%) of endometrial cell lines and 19/187 (10%) of primary uterine tumors. Mutations were seen primarily in tumors of the endometrioid histologic subtype (18/115 cases investigated, 16%). The majority of the somatic mutations identified were identical to germline activating mutations in FGFR2 and FGFR3 that cause Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and SADDAN syndrome. The two most common somatic mutations identified were S252W (in eight tumors) and N550K (in five samples). Four novel mutations were identified, three of which are also likely to result in receptor gain-of-function. Extensive functional analyses have already been performed on many of these mutations, demonstrating they result in receptor activation through a variety of mechanisms. The discovery of activating FGFR2 mutations in endometrial carcinoma raises the possibility of employing anti-FGFR molecularly targeted therapies in patients with advanced or recurrent endometrial carcinoma.

Apert syndrome was diagnosed in a newborn with typical facial and digital features whose only detected prenatal abnormality had been agenesis of the corpus callosum. This prompted a review of the central nervous system findings in all cases of Apert syndrome treated at the Craniofacial Center Boston Children's Hospital between 1978 and 2004. Two of 30 patients with Apert syndrome had prenatal identification of mild dilatation of the lateral cerebral ventricles and complete agenesis of the corpus callosum (ACC) documented with both ultrasound and MRI. Both had the common S252W mutation of FGFR2. Though cranial and orbital malformations typical of Apert were eventually seen in these fetuses in the third-trimester, even in retrospect, these were not detectable at mid second-trimester, ultrasound screening for congenital malformations. Hand malformations also went undetected in the second-trimester despite extensive imaging by experienced radiologists. We conclude that prenatal ultrasonographic identification of mild ventriculomegaly or ACC should stimulate a careful search for features of Apert syndrome and prompt follow-up imaging to look for bony abnormalities that have later onset. Prenatal molecular testing for Apert mutations should be considered in cases of mild ventriculomegaly and ACC.

Apert syndrome was diagnosed in a newborn with typical facial and digital features whose only detected prenatal abnormality had been agenesis of the corpus callosum. This prompted a review of the central nervous system findings in all cases of Apert syndrome treated at the Craniofacial Center Boston Children's Hospital between 1978 and 2004. Two of 30 patients with Apert syndrome had prenatal identification of mild dilatation of the lateral cerebral ventricles and complete agenesis of the corpus callosum (ACC) documented with both ultrasound and MRI. Both had the common S252W mutation of FGFR2. Though cranial and orbital malformations typical of Apert were eventually seen in these fetuses in the third-trimester, even in retrospect, these were not detectable at mid second-trimester, ultrasound screening for congenital malformations. Hand malformations also went undetected in the second-trimester despite extensive imaging by experienced radiologists. We conclude that prenatal ultrasonographic identification of mild ventriculomegaly or ACC should stimulate a careful search for features of Apert syndrome and prompt follow-up imaging to look for bony abnormalities that have later onset. Prenatal molecular testing for Apert mutations should be considered in cases of mild ventriculomegaly and ACC.