NTRK gene fusions are sporadic genetic alterations that can occur across tumor entities. Whereas they are quite rare in most solid tumors they are present at much higher frequencies in certain rare ...tumors such as infantile fibrosarcoma, congenital mesoblastic nephroma, secretory breast, or salivary gland carcinoma. NTRK gene fusions or TRK fusion proteins are considered strong oncogenic drivers. If NTRK gene fusions are detected, TRK inhibitors such as entrectinib and larotrectinib can be used regardless of the tumor entity. So far only larotrectinib is approved in the European Union. Both drugs have been shown to be effective and well tolerated in phase I and phase II studies. The low prevalence of TRK fusion-positive cancers poses challenges for diagnostic and clinical work-flows. On one hand, patients with NTRK gene fusions should be identified; on the other hand, epidemiological, histological, and resource-related aspects have to be taken into account. Based on these premises, we suggest a diagnostic algorithm for TRK fusion cancers and present current data on TRK inhibitors.
Background
Hepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are the most common malignant liver tumors in childhood. Both tumor types exhibit genetic and epigenetic alterations in the ...WNT/β-catenin signaling pathway, which is a key regulator of liver progenitor cells in embryonic development. The tumors demonstrate a high rate of β-catenin mutations and gene expression changes of several WNT antagonists. However, the role of the WNT inhibitory factor secreted frizzled-related protein 1 (SFRP1) has not been addressed in pediatric liver cancer so far.
Results
In our study, we investigated the gene expression level, DNA methylation status and functional relevance of SFRP1 in HB cell lines and in pediatric liver tumor patient samples. SFRP1 was downregulated due to DNA promoter methylation in all tested HB cell lines. Overexpression of SFRP1 in HB cell lines diminished tumor cell proliferation, colony formation and migration potential. In addition, the SFRP1-expressing HB cell lines showed reduced WNT/β-catenin signaling pathway activity and decreased expression of WNT target genes. To evaluate the utility of SFRP1 as a biomarker in pediatric liver cancer, we determined the gene expression level and DNA methylation status of SFRP1 in 45 pediatric liver tumor patient samples. The correlation analysis of different clinical parameters and tumor characteristics revealed a significant correlation of reduced SFRP1 expression with the presence of mutant β-catenin. The methylation status of SFRP1 was furthermore associated to a pediatric liver tumor type with HCC-like characteristics, TERT mutations and an older age at diagnosis.
Conclusion
Altogether, our data demonstrate that the epigenetic suppression of the WNT/β-catenin antagonist SFRP1 has an important impact on the malignant behavior of HB cells. Although SFRP1 methylation is a common event in HCC-like pediatric liver tumors, its potential as a prognostic or diagnostic biomarker needs to be further investigated.
NTRK
-Genfusionen sind seltene genetische Alterationen, die tumorentitätenübergreifend vorkommen können. Während sie in den meisten soliden Tumoren nur sehr niederfrequent vorkommen, lassen sie sich ...in bestimmten Tumoren wie dem infantilen Fibrosarkom, dem kongenitalen mesoblastischen Nephrom und dem sekretorischen Mamma- oder Speicheldrüsenkarzinom jedoch häufig nachweisen.
NTRK
-Genfusionen bzw. TRK-Fusionsproteine gelten als starke onkogene Treiber. Bei Nachweis von
NTRK
-Genfusionen können TRK-Inhibitoren unabhängig von der Tumorentität eingesetzt werden. Vertreter sind Entrectinib und Larotrectinib. Bislang ist nur Larotrectinib in der Europäischen Union zugelassen. Für beide wurden Wirksamkeit und Verträglichkeit in Phase-I- und Phase-II-Studien gezeigt. Die Seltenheit der TRK-Fusionstumoren stellt diagnostische und klinische Prozesse vor große Herausforderungen: Einerseits sollen alle Patienten mit TRK-Fusionstumoren identifiziert werden, andererseits sind epidemiologische und histologische Aspekte sowie Ressourcen zu berücksichtigen. Basierend auf diesen Punkten möchten wir einen Diagnosealgorithmus für TRK-Fusionstumoren vorschlagen, außerdem stellen wir aktuelle Daten zu den TRK-Inhibitoren vor.
Background: Hepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described ...to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification. Results: We examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature. Conclusion: These findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.
Enlarging tumor of the lateral chest wall in a 14-year-old boy Poch, Gabriela; Vokuhl, Christian; Klapper, Wolfram ...
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG,
05/2018, Volume:
16, Issue:
5
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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