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Bladder Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Fifty-eight significantly mutated genes have been identified; the main features are summarized in Figure 13.1. TP53 and cell cycle genes were mutated in 89% of tumors including TP53 in 48%, MDM2 over-expression in 25%, and RB mutations 17%, CDKN2a mutation/deletion 22%, CDKN1A in 11%. RAS/PI3K pathway was also frequently mutated (in ~70%). An unexpected major feature has been the frequency of chromatin remodeling genes with ten genes mutated at >5% frequency and occurring in over 50% of tumors, the significance of which is unclear. DNA repair genes are also found to be mutated in around 16% cases including ATM (14%), ERCC2 (9%), and RAD51 (2%). FGFR2/3 mutations have reported to occur in 15–20% of cases with the frequency being higher in lower-stage lower-grade tumors.
Craniofacial Regeneration—Bone
Published in Vincenzo Guarino, Marco Antonio Alvarez-Pérez, Current Advances in Oral and Craniofacial Tissue Engineering, 2020
Laura Guadalupe Hernandez, Lucia Pérez Sánchez, Rafael Hernández González, Janeth Serrano-Bello
Most recognizable craniofacial syndromes are monogenic Mendelian disorders, different mutations in the same gene. However, it is not a rule because, more than 7000 single-gene disorders have been identified in craniofacial disorders such as Stickler syndrome and the craniosynostosis syndromes involving different FGFR genes (FGFR1, FGFR2, FGFR3).
Oral and craniofacial disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Several specific genetic and clinical types of craniosynostosis exist, which are important to distinguish in genetic counselling. Gorlin's Syndromes of the Head and Neck (see Appendix 1) provides a detailed description. The principal types are listed in Table 17.3. Recognition of the different molecular defects (notably in fibroblast growth factor receptor 2) has been of great importance. All forms except Carpenter syndrome are autosomal dominant, with many cases (almost all in Apert syndrome) due to new mutation.
Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications
Published in Expert Review of Molecular Diagnostics, 2023
Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera
In GC, fibroblast growth factor receptor 2 (FGFR2) is the most frequently mutated member of the FGFR family, with mutations occurring in approximately 4.0% of advanced GC cases. Gene amplification is the predominant mechanism underlying FGFR2 overexpression in GC [33]. FGFR2 protein expression is evaluated by IHC [34]. Kim et al. performed a meta-analysis to evaluate the correlation of FGFR2 overexpression with survival in GC patients [23]. The authors demonstrated that patients with tumors overexpressing FGFR2 had significantly worse survival compared with GC patients with low FGFR2 expression (hazard ratio (HR) = 1.40, 95% CI: 1.25–1.58, P < 0.00001). The researchers also reported that FGFR2 was detected in the cytoplasm and at the cell membrane and was a potential therapeutic target. A Phase 2 study showed that bemarituzumab-β, a first-in-class humanized anti-FGFR2b IgG1 monoclonal antibody, demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS) (median 9.5 vs. 7.4 months, HR = 0.68, 95% CI: 0.44–1.04, P = 0.07) and OS (median not reached vs. 12.9 months, HR = 0.58, 95% CI: 0.35–0.95, P = 0.03) in combination with mFOLFOX compared with mFOLFOX alone in patients with unresectable locally advanced or metastatic GC with FGFR2b overexpression [35].
Past, present, and future of FGFR inhibitors in cholangiocarcinoma: from biological mechanisms to clinical applications
Published in Expert Review of Clinical Pharmacology, 2023
Elisabeth Amadeo, Federico Rossari, Francesco Vitiello, Valentina Burgio, Mara Persano, Stefano Cascinu, Andrea Casadei-Gardini, Margherita Rimini
After decades of chemotherapy application only precision medicine seems to become a more tangible option for cholangiocarcinoma as well. Indeed, in the last couple of years, many targetable mutations have been detected, i.e. IDH1, BRAFV600E, RET, BRCA 1/2, and HER2 [82], just to mention a few, widening the therapeutic options in such patients. Particular attention was drawn to the FGFR2 pathway, owing to the promising results of both laboratory and clinical studies. In fact, FGFR-I monotherapy mostly gave more benefits compared to standard chemotherapy in FGFR2 fusion-positive iCCAs. Contrary to the initial enthusiasm, there are still many ongoing challenges to establish FGFR-Is as the new standard of care, one of them being the rising of resistance mechanisms and poor early detection techniques. Further clinical studies are, thus, necessary to improve survival outcomes in such a complex disease.
Preclinical characterization of bemarituzumab, an anti-FGFR2b antibody for the treatment of cancer
Published in mAbs, 2021
Hong Xiang, Abigael G. Chan, Ago Ahene, David I. Bellovin, Rong Deng, Amy W. Hsu, Ursula Jeffry, Servando Palencia, Janine Powers, James Zanghi, Helen Collins
FGFR2b can be highly expressed in tumors through amplification of the FGFR2 gene or transcriptional upregulation of the FGFR2b isoform. As early as 1990, subsets of patients with gastric cancer were noted to have amplification of the FGFR2 gene.4 More recently, either overexpression of the FGFR2b receptor or amplification of FGFR2 have been identified as having prognostic importance in patients with gastric cancer.5–8 Overexpression of FGFR2b is significantly more common in the absence of amplification in advanced stage gastric cancer,9 and recent prospective evaluation in front line advanced and metastatic gastric cancer estimates the prevalence of FGFR2b overexpression at approximately 32%.10 Furthermore, alterations in the FGF/FGFR2 signaling pathway have been observed in other cancers as well, including breast, ovarian, endometrial, lung, and bile duct cancers.11–14 Thus, inhibition of FGFR2 signaling may be an effective mechanism of action for multiple cancer indications.5,6