Fibroblast growth factor receptor 3 gene (FGFR3) mutations in high-grade muscle-invasive urothelial bladder cancer in a Brazilian population: evaluation and prevalence

ABSTRACT Objective To understand the feasibility of FGFR3 tests in the Brazilian public health context, and to sample the mutational burden of this receptor in high-grade muscle invasive bladder cancer. Methods A total of 31 patients with high-grade muscle-invasive bladder cancer were included in the present study. Either transurethral resection of bladder tumor or radical cystectomy specimens were analyzed. Formalin-fixed paraffin-embedded tissue blocks were sectioned, hematoxylin and eosin stained, and histologic sections were reviewed. Total RNA was extracted using the RNeasy DSP formalin-fixed paraffin-embedded kit. Qualitative results were displayed in Rotor-Gene AssayManager software. Results Six patients were excluded. From the samples analyzed, four (16.7%) were considered inadequate and could not have their RNA extracted. Two patients presented FGFR3 mutations, accounting for 9.5% of material available for adequate analysis. The two mutations detected included a Y373C mutation in a male patient and a S249C mutation in a female patient. Conclusion FGFR3 mutations could be analyzed in 84% of our cohort and occurred in 9.5% of patients with high-grade muscle invasive bladder cancer in this Brazilian population. FGFR3 gene mutations are targets for therapeutic drugs in muscle-invasive bladder cancer. For this reason, know the frequency of these mutations can have a significant impact on public health policies and costs provisioning.

Novel Biomarkers for Prediction of Response to Preoperative Systemic Therapies in Gastric Cancer.

Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.

Genetically confirmed thanatophoric dysplasia with fibroblast growth factor receptor 3 mutation.

Thanatophoric dysplasia (TD), the most common lethal skeletal dysplasia, is a de novo genetic disease caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. "Thanatophoric" means "dead bearing" in Greek. Because FGFR3 is the main modulator of bone maturation, typical features of TD include short extremities, curved femur, clover-leaf skull, small narrow chest, and platyspondyly. TD can be classified into two subgroups according to the morphologic findings, with prominent curved femur suggesting type I TD (TD 1) and with marked clover-leaf skull and relatively straight long bones, favoring type II TD (TD 2). However, considering the genetic profiles, TD 1 and TD 2 could be confidently delineated. Here, we report five genotype-phenotype correlated autopsy cases of TD. Five cases had stigmata of TD on antenatal ultrasonography. Terminations were done at gestational age 16 to 28weeks, after family consultation. In autopsy, all fetuses showed short limbs and clover-leaf skull. The microscopic examination of the bones showed disorganized growth plate, consistent with TD. However, some differences existed in gross and microscopic findings between cases. In genetic analyses, three cases revealed missense mutation of Y373C, while the remaining two cases had missense mutation of S371C and S249C each. They were hot spot mutations of TD 1. A correlation between genotype and phenotype was not apparent due to the limited number of the cases. Therefore, a molecular work up to identify the mutation of FGFR3 is indispensable for TD diagnosis in the era of precision medicine for genetic consultation and future targeted therapy.

[Clinical analysis of 21 cases with short fetal femur in the third trimester].

Objective: To analyze the clinical features and to explore the etiology of short fetal femur during the third trimester. Methods: From January 2010 to June 2016, 21 singleton pregnancies with short fetal femur detected by ultrasonography during the third trimester were referred to the Chinese PLA General Hospital. Clinical data were collected, karyotype or single nucleotide polymorphism microarray was carried out to detect chromosomal abnormalities, and FGFR3 c.1138G>A mutation detection was carried out to detect achondroplasia (ACH) via invasive procedure, respectively. The deviation of femur length from the mean value of the gestational age in ultrasonography was expressed as the Z-score. The difference between ACH and isolated short femur (ISF, in the absence of associated structure abnormality or genetic abnormality) was then explored. Results: In the 21 fetuses, 11 had abnormal genetic test results(52%, 11/21), including 9 cases of ACH, 1 case of Ellis-van Creveld Syndrome and 1 case of Pallister-Killian syndrome. In the 10 ISF fetuses (48%, 10/21), 3 cases were fetal growth restriction, 1 was normal small for gestational age infant and 6 cases were unexplained. The median Z-scores for 9 cases of ACH and 10 cases of ISF in the third trimester were -5.04, -3.20, respectively. The short femur in ACH was more severe than in ISF (P=0.005) in the third trimester. Conclusions: The etiology of short fetal femur is complicated, including skeletal dysplasia, chromosomal abnormality, fetal growth restriction, as well as normal variants during fetal development. Genetic test should be considered during the antenatal consultation.

FGFR3 overexpression is prognostic of adverse outcome for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy.

BACKGROUND: Alterations in fibroblast growth factor receptor 3 (FGFR3) have been implicated in the pathogenesis of urothelial carcinoma. However, its clinicopathological significance has not been clearly established, especially in muscle-invasive bladder cancer (MIBC). OBJECTIVES: The aim of our study was to investigate the mutation and overexpression of FGFR3 in MIBC cases from radical cystectomy and to analyze the prognostic and predictive significance in the groups with or without adjuvant chemotherapy. METHODS AND MATERIALS: Study cohorts included 72 cases of MIBC including 42 patients who were treated with adjuvant chemotherapy. The mutation status of FGFR3 exons 7, 10, and 15 was investigated and protein expression was evaluated. The findings were analyzed for the association with relevant clinicopathological findings. RESULTS: FGFR3 mutations were found in 7 patients (9.7%) and were correlated with a pattern of papillary growth, moderate histologic grade (G2 vs. G3), and moderately advanced TNM stage (II-III vs. IV). FGFR3 protein overexpression was detected in 33 cases (45.8%) but was not associated with the relevant clinicopathological parameters. In patients treated with adjuvant chemotherapy, FGFR3 overexpression was correlated with shorter disease-free survival (P = 0.067, 95% confidence interval: 14.8-29.6, marginal significance) and overall survival (P = 0.035), remaining as a significant independent prognostic factor for disease-free survival and overall survival in multivariate analysis using Cox proportional hazards model. In patients without adjuvant chemotherapy, FGFR3 mutation or overexpression did not have prognostic significance in multivariate analysis. CONCLUSION: We report the FGFR3 alterations in MIBCs, and discuss their biological implication in subsets of patients. FGFR3 overexpression was predictive of adverse outcome in patients with adjuvant cisplatin-based chemotherapy after radical cystectomy. The utility of FGFR3 as a therapeutic target is suggested.

Successful birth with preimplantation genetic diagnosis using single-cell allele-specific PCR and sequencing in a woman with hypochondroplasia due to FGFR3 mutation (c.1620C>A, p.N540K).

Hypochondroplasia (HCH) is an autosomal dominant inherited skeletal dysplasia, usually caused by a heterozygous mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A 27-year-old HCH woman with a history of two consecutive abortions of HCH-affected fetuses visited our clinic for preimplantation genetic diagnosis (PGD). We confirmed the mutation in the proband (FGFR3:c.1620C>A, p.N540K), and established a nested allele-specific PCR and sequence analysis for PGD using single lymphocyte cells. We performed this molecular genetic analysis to detect the presence of mutation among 20 blastomeres from 18 different embryos, and selected 9 embryos with the wild-type sequence (FGFR3:c.1620C). A successful pregnancy was achieved through a frozen-thawed cycle and resulted in the full-term birth of a normal neonate. To the best of our knowledge, this is the first report of a successful pregnancy and birth using single-cell allele-specific PCR and sequencing for PGD in an HCH patient.