FGFR3::TACC3 fusions in head and neck carcinomas: a study of nine cases highlighting phenotypic heterogeneity, frequent HPV association, and a morphologically distinct subset in favor of a putative entity

Article

Author: Bell, Diana ; Antonescu, Cristina R ; Agaimy, Abbas ; Laco, Jan ; Dermawan, Josephine K ; Breimer, Gerben E ; Kester, Lennart A ; Bishop, Justin A ; Stoehr, Robert ; Rijken, Johannes A ; Cramer, Thomas ; Whaley, Rumeal D

AbstractThe FGFR3::TACC3 fusion has been reported in subsets of diverse cancers including urothelial and squamous cell carcinomas (SCC). However, the morphology of FGFR3::TACC3-positive head and neck carcinomas has not been well studied and it is unclear if this fusion represents a random event, or if it might characterize a morphologically distinct tumor type. We describe nine FGFR3::TACC3 fusion–positive head and neck carcinomas affecting six males and three females aged 38 to 89 years (median, 59). The tumors originated in the sinonasal tract (n = 4), parotid gland (n = 2), and one case each in the oropharynx, submandibular gland, and larynx. At last follow-up (9–21 months; median, 11), four patients developed local recurrence and/or distant metastases, two died of disease at 11 and 12 months, one died of other cause, one was alive with disease, and two were disease-free. Three of six tumors harbored high risk oncogenic HPV infection (HPV33, HPV18, one unspecified). Histologically, three tumors revealed non-keratinizing transitional cell-like or non-descript morphology with variable mixed inflammatory infiltrate reminiscent of mucoepidermoid or DEK::AFF2 carcinoma (all were HPV-negative), and three were HPV-associated (all sinonasal) with multiphenotypic (1) and non-intestinal adenocarcinoma (2) pattern, respectively. One salivary gland tumor showed poorly cohesive large epithelioid cells with prominent background inflammation and expressed AR and GATA3, in line with a possible salivary duct carcinoma variant. Two tumors were conventional SCC. Targeted RNA sequencing revealed an in-frame FGFR3::TACC3 fusion in all cases. This series highlights heterogeneity of head and neck carcinomas harboring FGFR3::TACC3 fusions, which segregates into three categories: (1) unclassified HPV-negative category, morphologically distinct from SCC and other entities; (2) heterogeneous group of HPV-associated carcinomas; and (3) conventional SCC. A driver role of the FGFR3::TACC3 fusion in the first category (as a potential distinct entity) remains to be further studied. In the light of available FGFR-targeting therapies, delineation of these tumors and enhanced recognition is recommended.

01 Feb 2025·Thoracic Cancer

A Comprehensive Analysis of FGF/FGFR Signaling Alteration in NSCLC: Implications in Prognosis and Microenvironment

Article

Author: Li, Leyao ; Li, Yuan ; Jia, Yun ; Wang, Shen ; Cai, Xu ; Huang, Ziling

ABSTRACTFibroblast Growth Factor (FGF) ligands and their receptor have been identified as the potent target in non–small cell lung cancer (NSCLC). However, the clinicopathological and microenvironmental characteristics of FGF/FGFR in NSCLC remain poorly elucidated. Here, we summarize 4656 NSCLCs and analyze clinicopathological features in 478 FGF/FGFR altered cases. AI analysis and multiplex immunofluorescence staining are used to reveal microenvironment features. First, around 10.27% NSCLC carry FGF/FGFR variant. Squamous cell carcinoma (41.95%) is much more than adenocarcinoma (8.32%). In 118 pathogenic variant (PV) cases, the most frequent variant is FGF/FGFR copy number increase (83.05%), the second is FGFR gene fusion (11.86%). Surprisingly, CCND1 always co‐amplifies with FGF19 (100.00%). Furthermore, FGF PV is an independent risk factor for poor outcomes (overall survival: HR = 3.781, disease‐free survival: HR = 3.340). And one‐third of FGFR3‐TACC3 fusion cases show clear cytoplasm in histology. Either CCND1/FGF19 co‐amplification or KRAS co‐mutation is closely related to cigarette exposure, and KRAS co‐mutation acts as an independent factor of poor prognosis. Finally, the FGF/FGFR1/NOTCH1 within RB1 variant group has a remarkably high ratio of inner‐tumor CD8+ T cell infiltration, non‐exhausted T cells, exhausted TCD8+PD‐1+LAG3− cells, and TRMCD8+CD69+CD103+cells. Overall, this study provides a comprehensive analysis of FGF/FGFR alteration in NSCLC. The FGF/FGFR alteration mainly arises in squamous cell carcinoma. Both FGF PV and KRAS are the independent factors for poor prognosis. To our knowledge, this is the first report to describe an inflamed microenvironment recruited by NOTCH1/RB1 co‐mutation, indicating potential benefit from immunotherapy.

01 Jan 2025·Mutation Research - Reviews in Mutation Research

The landscape of FGFR-TACC fusion in adult glioblastoma: From bench to bedside

Review

Author: Wang, Zheng ; Liu, Jing

Glioblastoma (GBM) is a lethal central nervous system tumor, characterized by extensive genomic alterations and high intra-tumoral heterogeneity. Gene fusions, derived from chromosomal translocations, deletions, and inversions, were increasingly recognized as key carcinogenic events, with the highest frequency of FGFR-TACC fusion in glioblastoma. As reported, FGFR3-TACC3 fusion mostly coexists with wild-type IDH status, and associates with better prognosis. Mechanistically, FGFR3-TACC3 fusions can constitutively activate non-canonical FGFR downstream pathways, induce aneuploidy, and participate in mitochondrial metabolism, thereby promoting cell proliferation and tumorigenesis. These functions, whether based on FGFR3 phosphorylation or not, are predominantly attributed to the specific domain of TACC3 that involved in regulating the localization and activation of fusion products. Several preclinical studies and clinical trials are being performed to evaluate the efficacy and safety of the FGFR-TACC fusion as a personalised therapeutic target, including the treatments with tyrosine kinase inhibitors, metabolic inhibitors, HSP90 inhibitors, coiled-coil peptide-mimetics, and targeted protein degraders. A subset of populations with FGFR-TACC-positive glioblastoma, after refined molecular screening strategies, may benefit from targeted therapies. Despite major progress in biotechnology, our understanding on the role of fusion events in glioblastoma represented by the FGFR-TACC is still in its infancy. Here, we highlight recent progress on FGFR-TACC fusion in human glioblastoma, emphasizing their molecular mechanisms and potential clinical value.

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