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The Tetralogy of Fallot (TOF), the most prevalent form of cyanotic congenital heart disease, stems from abnormal development of the outflow tract during embryogenesis. Despite the crucial role played by primary cilia in heart development, there is currently insufficient evidence to establish a causal relationship between defects in genes related to primary cilia and non-syndromic TOF. Here, we performed Sanger sequencing on 131 Chinese patients diagnosed with TOF and identified a splicing variant (c.683-1G>C) in the EFCAB7 gene. This splicing variant triggered exon skipping, leading to the production of a non-functional protein both in vitro and in vivo. Mice carrying this variant exhibited abnormal cardiac development, impaired ciliogenesis, disrupted Hedgehog signaling, and hindered Shh/Gli pathway activity. Through integration of CUT&Tag data on Glis and bulk RNA-seq profiles of embryonic hearts at E10.5, we found that transcriptional downregulation of Gli target genes, including Myh6, Zfpm1 and Nkx2-5, is a consequence of Shh signaling inhibition. Our findings implicate EFCAB7 as a potential causative gene for TOF, underscoring the indispensable function of primary cilia in the intricate process of cardiac septation during heart development., Competing Interests: Competing interests The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Except for gene fusions, FGFR2 genetic alterations in intrahepatic cholangiocarcinomas (ICCs) have received limited attention, leaving patients harboring activating FGFR2 gene mutations with inadequate access to targeted therapies., Experimental Design: We sought to survey FGFR2 genetic alterations in ICC and pan-cancers using fluorescence in situ hybridization and next-generation sequencing. We conducted an analysis of the clinical and pathological features of ICCs with different FGFR2 alterations, compared FGFR2 lesion spectrum through public databases and multicenter data, and performed cellular experiments to investigate the oncogenic potential of different FGFR2 mutants., Results: FGFR2 gene fusions were identified in 30 out of 474 ICC samples, while five FGFR2 genetic alterations aside from fusion were present in 290 ICCs. The tumors containing FGFR2 translocations exhibited unique features, which we designated as the "FGFR2 fusion subtypes of ICC". Molecular analysis revealed that FGFR2 fusions were not mutually exclusive with other oncogenic driver genes/mutations, whereas FGFR2 in-frame deletions and site mutations often co-occurred with TP53 mutations. Multicenter and pan-cancer studies demonstrated that FGFR2 in-frame deletions were more prevalent in ICCs (0.62%) than in other cancers, and were not limited to the extracellular domain. We selected representative FGFR2 genetic alterations, including in-frame deletions, point mutations, and frameshift mutations, to analyze their oncogenic activity and responsiveness to targeted drugs. Cellular experiments revealed that different FGFR2 genetic alterations promoted ICC tumor growth, invasion, and metastasis but responded differently to FGFR-selective small molecule kinase inhibitors (SMKIs)., Conclusions: FGFR2 oncogenic alterations have different clinicopathological features and respond differently to SMKIs., (© 2023. The Author(s).)

Background: Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Metastasis and relapse are the leading causes of death in MB patients. The initiation of the SHH subgroup of MB (SHH-MB) is due to the aberrant activation of Sonic Hedgehog (Shh) signaling. However, the mechanisms for its metastasis are still unknown., Results: AMP-dependent protein kinase (AMPK) restrains the activation of Shh signaling pathway, thereby impeding the proliferation of SHH-MB cells. More importantly, AMPK also hinders the growth and metastasis of SHH-MB cells by regulating NF-κB signaling pathway. Furthermore, Vismodegib and TPCA-1, which block the Shh and NF-κB pathways, respectively, synergistically restrained the growth, migration, and invasion of SHH-MB cells., Conclusions: This work demonstrates that AMPK functions through two signaling pathways, SHH-GLI1 and NF-κB. AMPK-NF-κB axis is a potential target for molecular therapy of SHH-MB, and the combinational blockade of NF-κB and Shh pathways confers synergy for SHH-MB therapy., (© 2023. The Author(s).)