The comparison of morphology, expression, epigenetic changes and mutations of HNF1B in solid tumors and non-neoplastic lesions.

Introduction HNF1B is a tissue-specific transcription factor, which plays a crucial role in the embryological development of a number of organs, especially kidneys, gastrointestinal system, pancreas and billiary system. While the significance of HNF1B in the development of urinary tract malformations has already been well described, its role in the pathogenesis of solid tumors has not yet been elucidated. Based on the current data it seems that depending on the type of individual tumor HNF1B can either act as an oncogene or a tumor suppressor. However, the precise mechanism of how it exerts its influence is still unclear. Aims: The thesis focuses on expanding the knowledge of the significance of HNF1B changes in selected solid tumors and non-neoplastic lesions. The individual goals include: 1) determining the role which HNF1B plays in the pathogenesis of these lesions, 2) evaluating the significance of HNF1B for differential diagnosis, 3) analysis of the prognostic and predictive meaning of HNF1B, 4) mutation analysis of the HNF1B gene in all the tumor and non-tumor tissues with the aim to identify novel pathogenic mutations, 5) methylation analysis of the HNF1B promoter. Material and methods: Immunohistochemical examination with the antibody against HNF1B was performed on 516 samples of tumor and..

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Desmoplastic Small Round Cell Tumor of the Uterus: A Report of Molecularly Confirmed Case with EWSR1-WT1 Fusion

We report a case of a 49-year-old female with desmoplastic small round cell tumor of the uterus (DSRCT). Histologically, in some areas the tumor showed typical features with ample desmoplastic stroma, while in other areas the tumor cells diffusely infiltrated myometrium with only focal desmoplastic reaction. Immunohistochemically, the tumor cells showed diffuse positivity for desmin, CD56, CD57, EMA and cyclin D1. Focal positivity was present for antibodies against cytokeratin AE1/3, BerEP4, NSE, IFITM1 and CD10. The WT-1 antibody (against the N-terminus) showed cytoplasmic positivity in some tumor cells, while the nuclei were negative. P53 expression was wild-type. The Ki-67 index (MIB1 antibody) was about 55%. Other markers examined including transgelin, myogenin, synaptophysin, chromogranin, h-caldesmon, PAX8, and CD117 were all negative. NGS analysis revealed a fusion transcript of the EWSR1 and WT1 genes. DSRCT of the uterus is a rare neoplasm, as only two cases have been reported so far. However, only one of these cases was examined molecularly with a confirmation of the characteristic EWSR1-WT1 fusion. We report a second case of molecularly confirmed DSRCT of the uterus and discuss its clinical features, differential diagnosis and the significance of molecular testing

Complex tumours genomic and transcriptomic analysis in uterine tumours resembling ovarian sex cord tumours (UTROSCT).

Background & objectives: UTROSCT is a rare entity. Most tumours behave in a benign fashion, but clinically aggressive neoplasms have been described. Our aim was to perform a comprehensive genomic and transcriptomic analysis in a series of UTROSCT to reveal clinically relevant alterations. Methods: DNA and RNA isolated from 30 UTROSCT were analysed using capture DNA NGS analysis (KAPA HyperPlus kit and a panel of 788 genes/gene parts; 2044 kbp; Roche) and transcriptome RNA-Seq (KAPA RNA HyperPrep kit; Roche), and pair-end sequenced on Next- Seq 500 or NovaSeq (Illumina). Only likely pathogenic or pathogenic (class 4/5) mutations and gene fusions were evaluated. Results: The analyses of our sample set revealed the presence of several recurrent gene fusions in the majority of the cases, including NCOA2/3. Moreover, whole transcriptome RNA-Seq revealed additional rare gene fusions such as COL6A3::FAM13B. Other alterations detected included rare class 4/5 mutations in CHEK2 and RECQL4. Conclusion: Our complex study of the molecular alterations in UTRO- SCT has revealed potentially signifcant gene fusions and genetic alter- ations in these tumours, some of which may be clinically actionable