{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nFibroblast growth factor receptor 2 (FGFR2) is a receptor tyrosine kinase that plays a pivotal role in normal development and tissue homeostasis. Its activity is tightly controlled by mechanisms such as alternative splicing—which generates the epithelial FGFR2b and mesenchymal FGFR2c isoforms to confer distinct ligand‐binding specificities—and by intramolecular regulatory features (for example, an autoinhibitory “molecular brake” and modulatory interactions with adaptor proteins). Structural and functional studies have revealed that mutations affecting key extracellular or kinase domain regions of FGFR2 can disrupt this delicate regulation and lead to developmental disorders such as craniosynostosis and Apert syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of breast cancer, genome‐wide association studies have pinpointed single nucleotide polymorphisms (SNPs) in an intronic region of FGFR2 that associate with a moderately increased risk—particularly for estrogen receptor–positive tumors. Functional analyses support a model in which these noncoding variants alter transcription factor binding (for example, sites for Oct‐1/Runx2 and C/EBPβ) and consequently upregulate FGFR2 expression, thereby enhancing proliferative signaling in breast epithelium. Additional studies demonstrate that FGFR2 signaling integrates with nuclear receptor networks and is further modulated by microRNAs (such as miR‑125b), collectively influencing cell proliferation and differentiation during tumor initiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in normal physiology and breast cancer predisposition, FGFR2 is a recurrent target of oncogenic alterations in a variety of malignancies. Activating mutations, gene amplifications, and fusion events involving FGFR2 have been identified in cancers such as endometrial carcinoma, gastric carcinoma, intrahepatic cholangiocarcinoma, lung, and even colorectal tumors. In these settings, aberrant FGFR2 signaling—often mediated through downstream MAPK, PI3K, and EGFR family cascades—drives tumor cell proliferation, survival, and even angiogenesis via an FGF‑2/FGFR2 axis. Notably, FGFR2 fusions (for example, FGFR2–AHCYL1, FGFR2–BICC1, or FGFR2–PPHLN1) have emerged as actionable targets in cholangiocarcinoma, and preclinical models demonstrate that selective FGFR inhibitors can overcome primary and acquired resistance arising from secondary kinase mutations. Moreover, in some tumors FGFR2 pathway activity interplays with cancer stem cell–like gene expression programs and influences epithelial–mesenchymal transitions, underlining its diverse contributions to oncogenesis and therapy resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shih-hsin Kan, Navaratnam Elanko, David Johnson, et al. 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