Cíl: Zjistit míru metylací DNA vybraných genových promotorů u jednotlivých typů hyperplazie endometria ve srovnání s normální endometriální tkání. Soubor a metodika: Byla použita MS-MLPA (multiplex ligation-dependent probe amplification). Porovnáno bylo celkem 120 vzorků tkáně endometria; 40 vzorků s atypickou hyperplazií endometria, 40 vzorků s hyperplazií endometria bez atypií a 40 kontrolních vzorků tkáně zdravého endometria. Výsledky a závěry: Rozdíly v metylaci DNA mezi jednotlivými skupinami byly zjištěny v genech TWIST1, GATA4, MUS81 a NTRK1 (TWIST1: atypická hyperplazie 67,5 %, benigní hyperplazie 2,5 %, normální endometrium 22,5 %; p < 0,00001; GATA4: atypická hyperplazie 95,0 %, benigní hyperplazie 65,0 %, normální endometrium 22,5 %; p < 0,00001; MUS81: atypická hyperplazie 57,5 %, benigní hyperplazie 22,5 %, normální endo-metrium 5,0 %; p < 0,00001; NTRK1: atypická hyperplazie 65,0 %, benigní hyperplazie 27,5 %, normální endometrium 10 %; p < 0,00001). U genů TWIST1, GATA4, MUS81 a NTRK1 byla pozorována vyšší míra metylace u vzorků s atypickou hyperplazií endometria v porovnání se vzorky zdravého endometria a dále byla vyšší míra metylace pozorována u vzorků s atypickou hyperplazií endometria v porovnání se vzorky benigní hyperplazie endometria. Metylace DNA u tumor supresorových genů TWIST1, GATA4, MUS81 a NTRK1 se uplatňuje v patogenezi atypické hyperplazie endometria.

Objective: To investigate DNA methylation of specific tumor suppressor genes in endometrial hyperplasia compared to normal endometrial tissue. File and methodology: To search for epigenetic events, methylation-specific multiplex ligation-dependent probe amplification was employed to compare the methylation status of 40 tissue samples with atypical endometrial hyperplasia, 40 tissue samples with endometrial hyperplasia without atypia, and 40 control tissue samples with a normal endometrium. Results and conclusion: Differences in DNA methylation among the groups were found in TWIST1, GATA4, MUS81, and NTRK1 genes (TWIST1: atypical hyperplasia 67.5%, benign hyperplasia 2.5%, normal endometrium 22.5%; P < 0.00001; GATA4: atypical hyperplasia 95%, benign hyperplasia 65%, normal endometrium 22.5%; P < 0.00001; MUS81: atypical hyperplasia 57.5%, benign hyperplasia 22.5%, normal endometrium 5%; P < 0.00001; NTRK1: atypical hyperplasia 65%, benign hyperplasia 27.5%, normal endometrium 10%; P < 0.00001). Higher methylation rates were observed for the tumor suppressor genes of TWIST1, GATA4, MUS81, and NTRK1 in samples with atypical endometrial hyperplasia compared to samples with normal endometrial tissue, and higher methylation rates were found in samples with atypical endometrial hyperplasia compared to samples of benign endometrial hyperplasia. DNA methylation of TWIST1, GATA4, MUS81, and NTRK1 is involved in the pathogenesis of atypical endometrial hyperplasia.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• endonukleasy genetika   MeSH
• hyperplazie endometria * genetika   metabolismus   patologie   MeSH
• jaderné proteiny genetika   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• metylace DNA MeSH
• receptor trkA genetika   MeSH
• transkripční faktor GATA4 genetika   metabolismus   MeSH
• transkripční faktor Twist genetika   MeSH
• tumor supresorové geny MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

Previously, we reported a family in which bipolar disorder (BD) co-segregates with a Mendelian kidney disorder linked to 1q22. The causative renal gene was later identified as MUC1. Genome-wide linkage analysis of BD in the family yielded a peak at 1q22 that encompassed the NTRK1 and MUC1 genes. NTRK1 codes for TrkA (Tropomyosin-related kinase A) which is essential for development of the cholinergic nervous system. Whole genome sequencing of the proband identified a damaging missense mutation, E492K, in NTRK1. Induced pluripotent stem cells were generated from family members, and then differentiated to neural stem cells (NSCs). E492K NSCs had reduced neurite outgrowth. A conditional knock-in mouse line, harboring the point mutation in the brain, showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor. These results are consistent with the cholinergic hypothesis of depression. They imply that the NTRK1 E492K mutation, impairs cholinergic neurotransmission, and may convey susceptibility to bipolar disorder.

• MeSH
• bipolární porucha * genetika   MeSH
• deprese MeSH
• mutace MeSH
• myši MeSH
• nemoci ledvin * MeSH
• receptor trkA * genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Ovarian cancer is the leading cause of death from gynaecologic tumours, but the molecular and especially epigenetic events underlying the transformation are poorly understood. Various methylation changes have been identified and show promise as potential cancer biomarkers. The aim of this study was to investigate promoter methylation of selected tumour suppressor genes in ovarian cancer by comparison with normal ovarian tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification to compare the methylation status of 44 tissue samples of ovarian cancer with 30 control samples. Using a 20% cut-off for methylation, we observed significantly higher methylation in genes NTKR1, GATA4 and WIF1 in the ovarian cancer group compared with the control group. These findings could potentially be used in screening of ovarian cancer, and may have implications for future chemotherapy based on epigenetic changes.

• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA genetika   MeSH
• mladý dospělý MeSH
• nádorové supresorové proteiny genetika   metabolismus   MeSH
• nádory vaječníků genetika   patologie   MeSH
• promotorové oblasti (genetika) * MeSH
• receptor trkA genetika   metabolismus   MeSH
• represorové proteiny genetika   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• transkripční faktor GATA4 genetika   metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

• MeSH
• dítě MeSH
• dospělí MeSH
• fibrosarkom * genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• lidé MeSH
• lokální recidiva nádoru genetika   MeSH
• nádorové biomarkery genetika   analýza   MeSH
• nádory měkkých tkání * genetika   MeSH
• nádory z pojivové a měkké tkáně * MeSH
• protoonkogenní proteiny B-Raf genetika   MeSH
• receptor trkA genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• entrectinib,
• MeSH
• antitumorózní látky aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• benzamidy aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba MeSH
• indazoly aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• inhibitory proteinkinas * aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• receptor trkA genetika   MeSH
• Check Tag
• lidé MeSH

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

• MeSH
• adenokarcinom diagnóza   genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory tračníku diagnóza   genetika   patologie   MeSH
• následné studie MeSH
• onkogenní fúze MeSH
• receptor trkA genetika   metabolismus   MeSH
• receptor trkB genetika   metabolismus   MeSH
• receptor trkC genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Larotrectinib je prvním registrovaným léčivým přípravkem protinádorové agnostické léčby pro tumory s fúzemi genů NTRK. Publikovaná analýza 159 dospělých i pediatrických pacientů se solidními tumory s fúzí NTRK léčených larotrectinibem prokázala medián trvání léčebné odpovědi 35,2 měsíce a medián doby do progrese onemocnění 28,3 měsíce. Jednalo se o značně heterogenní skupinu pokročilých předléčených nádorů. Larotrectinib má dobrý bezpečnostní profil; dávka byla redukována u 8 % nemocných a k přerušení terapie došlo u 2 % pacientů z důvodů nežádoucích účinků.

Larotrectinib is a registered anticancer drug for antitumor therapy for tumors with NTRK gene fusions. A published analysis of 159 adult and pediatric patients with solid NTRK fusion tumors treated with larotrectinib showed a median duration of response of 35.2 months and a median time to disease progression of 28.3 months. These were highly heterogeneous groups of advanced pretreated tumors. Larotrectinib has a good safety profile; the dose was reduced in 8% of patient, in 2% due to side effects.

• MeSH
• fúze genů MeSH
• lidé MeSH
• mutace * MeSH
• protinádorové látky imunologicky aktivní * škodlivé účinky   terapeutické užití   MeSH
• receptor trkA genetika   terapeutické užití   MeSH
• receptor trkB genetika   terapeutické užití   MeSH
• receptor trkC genetika   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

Background: Pediatric papillary thyroid carcinoma (PTC) is a rare malignancy, but with increasing incidence. Pediatric PTCs have distinct clinical and pathological features and even the molecular profile differs from adult PTCs. Somatic point mutations in pediatric PTCs have been previously described and studied, but complex information about fusion genes is lacking. The aim of this study was to identify different fusion genes in a large cohort of pediatric PTCs and to correlate them with clinical and pathological data of patients. Methods: The cohort consisted of 93 pediatric PTC patients (6-20 years old). DNA and RNA were extracted from fresh frozen tissue samples, followed by DNA and RNA-targeted next-generation sequencing analyses. Fusion gene-positive samples were verified by real-time polymerase chain reaction. Results: A genetic alteration was found in 72/93 (77.4%) pediatric PTC cases. In 52/93 (55.9%) pediatric PTC patients, a fusion gene was detected. Twenty different types of RET, NTRK3, ALK, NTRK1, BRAF, and MET fusions were found, of which five novel, TPR/RET, IKBKG/RET, BBIP1/RET, OPTN/BRAF, and EML4/MET, rearrangements were identified and a CUL1/BRAF rearrangement that has not been previously described in thyroid cancer. Fusion gene-positive PTCs were significantly associated with the mixture of classical and follicular variants of PTC, extrathyroidal extension, higher T classification, lymph node and distant metastases, chronic lymphocytic thyroiditis, and frequent occurrence of psammoma bodies compared with fusion gene-negative PTCs. Fusion-positive patients also received more doses of radioiodine therapy. The most common fusion genes were the RET fusions, followed by NTRK3 fusions. RET fusions were associated with more frequent lymph node and distant metastases and psammoma bodies, and NTRK3 fusions were associated with the follicular variant of PTC. Conclusions: Fusion genes were the most common genetic alterations in pediatric PTCs. Fusion gene-positive PTCs were associated with more aggressive disease than fusion gene-negative PTCs.

• MeSH
• bodová mutace MeSH
• dítě MeSH
• fenotyp MeSH
• fúze genů * MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory štítné žlázy genetika   patologie   terapie   MeSH
• papilární karcinom štítné žlázy genetika   patologie   terapie   MeSH
• prognóza MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• protoonkogenní proteiny c-met genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• receptor trkA genetika   MeSH
• receptor trkC genetika   MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• finanční podpora výzkumu jako téma MeSH
• mozkový neurotrofický faktor genetika   MeSH
• myši MeSH
• nervový růstový faktor genetika   metabolismus   MeSH
• neurony aferentní metabolismus   MeSH
• receptor trkA genetika   metabolismus   MeSH
• receptor trkC genetika   metabolismus   MeSH
• signální transdukce MeSH
• Vater-Paciniho tělíska růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

Fúzní translokace genů NTRK se vzácně vyskytují u širokého spektra solidních a hematologických nádorů. Entrectinib je jednou z možností léčby pacientů se solidními nádory s fúzní translokací NTRK nebo nemalobuněčným plicním karcinomem s fúzní translokací onkogenu ROS1. Je to vysoce účinný lék s dobrou biologickou dostupností, a to i v centrálním nervovém systému. Entrectinib je obvykle dobře snášen. V České republice je v současnosti k dispozici v rámci specifického léčebného programu.

• Klíčová slova
• entrectinib,
• MeSH
• benzamidy aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• fúzní onkogenní proteiny antagonisté a inhibitory   genetika   MeSH
• indazoly škodlivé účinky   terapeutické užití   MeSH
• inhibitory proteinkinas * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• receptor trkA * antagonisté a inhibitory   MeSH
• receptor trkB antagonisté a inhibitory   MeSH
• receptor trkC antagonisté a inhibitory   MeSH
• srdeční selhání chemicky indukované   etiologie   MeSH
• Check Tag
• lidé MeSH