PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.
- MeSH
- Child MeSH
- Adult MeSH
- Gene Fusion MeSH
- Oncogene Proteins, Fusion * genetics MeSH
- Glioma * genetics pathology mortality therapy MeSH
- Protein Kinase Inhibitors therapeutic use MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Glycoproteins MeSH
- Adolescent MeSH
- Young Adult MeSH
- Central Nervous System Neoplasms * genetics therapy mortality pathology MeSH
- Child, Preschool MeSH
- Prognosis MeSH
- Pyrazoles therapeutic use MeSH
- Pyrimidines therapeutic use MeSH
- Receptor, trkA * genetics antagonists & inhibitors MeSH
- Receptor, trkB genetics antagonists & inhibitors MeSH
- Receptor, trkC genetics antagonists & inhibitors MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Child, Preschool MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
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-Binding Proteins genetics MeSH
- Endonucleases genetics MeSH
- Endometrial Hyperplasia * genetics metabolism pathology MeSH
- Nuclear Proteins genetics MeSH
- Clinical Studies as Topic MeSH
- Humans MeSH
- DNA Methylation MeSH
- Receptor, trkA genetics MeSH
- GATA4 Transcription Factor genetics metabolism MeSH
- Twist-Related Protein 1 genetics MeSH
- Genes, Tumor Suppressor MeSH
- Check Tag
- Humans MeSH
- Female 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
- Child MeSH
- Adult MeSH
- Fibrosarcoma * genetics pathology MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Humans MeSH
- Neoplasm Recurrence, Local genetics MeSH
- Biomarkers, Tumor genetics analysis MeSH
- Soft Tissue Neoplasms * genetics MeSH
- Neoplasms, Connective and Soft Tissue * MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Receptor, trkA genetics MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- entrectinib,
- MeSH
- Benzamides administration & dosage pharmacology therapeutic use MeSH
- Oncogene Proteins, Fusion genetics MeSH
- Gene Rearrangement MeSH
- Indazoles administration & dosage pharmacology therapeutic use MeSH
- Protein Kinase Inhibitors * administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Neoplasms * drug therapy MeSH
- Antineoplastic Agents administration & dosage pharmacology therapeutic use MeSH
- Receptor, trkA genetics MeSH
- Check Tag
- Humans 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
- Adenocarcinoma diagnosis genetics pathology MeSH
- Oncogene Proteins, Fusion genetics metabolism MeSH
- Immunohistochemistry MeSH
- Middle Aged MeSH
- Humans MeSH
- Membrane Glycoproteins genetics metabolism MeSH
- Biomarkers, Tumor genetics metabolism MeSH
- Colonic Neoplasms diagnosis genetics pathology MeSH
- Follow-Up Studies MeSH
- Oncogene Fusion MeSH
- Receptor, trkA genetics metabolism MeSH
- Receptor, trkB genetics metabolism MeSH
- Receptor, trkC genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Staging MeSH
- Receptor Protein-Tyrosine Kinases genetics metabolism MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article 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.
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.
- Keywords
- entrectinib,
- MeSH
- Benzamides administration & dosage pharmacology adverse effects MeSH
- Oncogene Proteins, Fusion antagonists & inhibitors genetics MeSH
- Indazoles adverse effects therapeutic use MeSH
- Protein Kinase Inhibitors * administration & dosage pharmacology adverse effects MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Receptor, trkA * antagonists & inhibitors MeSH
- Receptor, trkB antagonists & inhibitors MeSH
- Receptor, trkC antagonists & inhibitors MeSH
- Heart Failure chemically induced etiology MeSH
- Check Tag
- Humans 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
- Point Mutation MeSH
- Child MeSH
- Phenotype MeSH
- Gene Fusion * MeSH
- Genetic Predisposition to Disease MeSH
- Gene Rearrangement MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Biomarkers, Tumor genetics MeSH
- Thyroid Neoplasms genetics pathology therapy MeSH
- Thyroid Cancer, Papillary genetics pathology therapy MeSH
- Prognosis MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- Proto-Oncogene Proteins c-met genetics MeSH
- Proto-Oncogene Proteins c-ret genetics MeSH
- Receptor, trkA genetics MeSH
- Receptor, trkC genetics MeSH
- Age Factors MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't 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
- Gene Fusion MeSH
- Humans MeSH
- Mutation * MeSH
- Antineoplastic Agents, Immunological * adverse effects therapeutic use MeSH
- Receptor, trkA genetics therapeutic use MeSH
- Receptor, trkB genetics therapeutic use MeSH
- Receptor, trkC genetics therapeutic use MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
- MeSH
- Survival Analysis MeSH
- Anaplastic Lymphoma Kinase genetics metabolism MeSH
- Epigenomics methods MeSH
- Glioma classification genetics metabolism MeSH
- Infant MeSH
- Humans MeSH
- DNA Methylation * MeSH
- Brain Neoplasms classification genetics metabolism MeSH
- Infant, Newborn MeSH
- Proto-Oncogene Proteins c-met genetics metabolism MeSH
- Proto-Oncogene Proteins genetics metabolism MeSH
- Receptor, trkA genetics metabolism MeSH
- Gene Expression Regulation, Neoplastic * MeSH
- Exome Sequencing methods MeSH
- Receptor Protein-Tyrosine Kinases genetics metabolism MeSH
- Protein-Tyrosine Kinases genetics metabolism MeSH
- Check Tag
- Infant MeSH
- Humans MeSH
- Male MeSH
- Infant, Newborn MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
