Adult granulosa cell tumors (AGCTs) of the ovary are characterized by their propensity for late recurrences and are primarily managed surgically due to the limited efficacy of systemic treatment. The FOXL2 p.C134W somatic mutation has been identified in ∼95% of AGCT cases, and TERT promoter alterations have been linked to worse overall survival. This study highlights the potential prognostic significance of FOXO1 mutations, suggesting that they may be associated with poorer overall survival and shorter time to recurrence. A total of 183 primary AGCTs and 44 recurrences without corresponding primary tumors were analyzed. The primary AGCTs were categorized into 3 groups: 77 nonrecurrent tumors, 18 tumors that later recurred (including 9 cases with matched primary-recurrence pairs), and 88 tumors with unknown recurrence status. Targeted next-generation sequencing was conducted on 786 cancer-related genes to investigate their genetic profile. The study aimed to identify the molecular alterations associated with AGCT pathogenesis and recurrence rate, comparing primary versus recurrent tumors, and primary recurrent versus primary nonrecurrent cases. Our findings confirmed the high prevalence (99%) of the FOXL2 p.C134W mutation in AGCTs. Secondary truncating FOXL2 mutations were observed in 5% of cases. Two cases with typical AGCT morphology were FOXL2 wild-type, harboring mutations in KRAS or KMT2D instead, suggesting alternative genetic pathways. TERT promoter mutations were found in 43% of cases, more frequently in recurrences. Other recurrent mutations detected in the cohort included KMT2D (10%), FOXO1 (7%), CHEK2 (5%), TP53 (3.5%), PIK3CA (3.5%), and AKT1 (3%). Two recurrent, FOXL2-mutated cases also carried DICER1 mutations. One tumor exhibited MSI-high status and a tumor mutation burden of 19 mut/Mb.Our results indicate the need for further investigation into the role of FOXO1 as a potential prognostic marker in AGCTs.

• MeSH
• dospělí MeSH
• forkhead box protein O1 * genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * genetika   MeSH
• mutace * MeSH
• nádor z folikulárních buněk * genetika   patologie   MeSH
• nádory vaječníků * genetika   patologie   MeSH
• prognóza MeSH
• progrese nemoci MeSH
• protein FOXL2 genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• telomerasa genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of Forkhead box protein O1 (FoxO1) transcription factor, which induces expression of Rictor, an assembly protein for the mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knockout or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. The FoxO1/Rictor/pAktS473 axis represents an early nongenetic adaptation to B cell receptor (BCR) inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T cell factors (CD40L, IL-4, and IL-21).

• MeSH
• adenin * analogy a deriváty   farmakologie   MeSH
• chronická lymfatická leukemie * farmakoterapie   metabolismus   genetika   patologie   MeSH
• forkhead box protein O1 * metabolismus   genetika   MeSH
• fosforylace MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové proteiny metabolismus   genetika   MeSH
• piperidiny * farmakologie   MeSH
• protein RICTOR * genetika   metabolismus   MeSH
• proteinkinasa BTK metabolismus   genetika   antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-akt * metabolismus   genetika   MeSH
• pyrazoly * farmakologie   MeSH
• pyrimidiny * farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Recirculation of chronic lymphocytic leukemia (CLL) cells between the peripheral blood and lymphoid niches plays a critical role in disease pathophysiology, and inhibiting this process is one of the major mechanisms of action for B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib. Migration is a complex process guided by chemokine receptors and integrins. However, it remains largely unknown how CLL cells integrate multiple migratory signals while balancing survival in the peripheral blood and the decision to return to immune niches. Our study provided evidence that CXCR4/CD5 intraclonal subpopulations can be used to study the regulation of migration of CLL cells. We performed RNA profiling of CXCR4dimCD5bright vs CXCR4brightCD5dim CLL cells and identified differential expression of dozens of molecules with a putative function in cell migration. GRB2-associated binding protein 1 (GAB1) positively regulated CLL cell homing capacity of CXCR4brightCD5dim cells. Gradual GAB1 accumulation in CLL cells outside immune niches was mediated by FoxO1-induced transcriptional GAB1 activation. Upregulation of GAB1 also played an important role in maintaining basal phosphatidylinositol 3-kinase (PI3K) activity and the "tonic" AKT phosphorylation required to sustain the survival of resting CLL B cells. This finding is important during ibrutinib therapy, because CLL cells induce the FoxO1-GAB1-pAKT axis, which represents an adaptation mechanism to the inability to home to immune niches. We have demonstrated that GAB1 can be targeted therapeutically by novel GAB1 inhibitors, alone or in combination with BTK inhibition. GAB1 inhibitors induce CLL cell apoptosis, impair cell migration, inhibit tonic or BCR-induced AKT phosphorylation, and block compensatory AKT activity during ibrutinib therapy.

• MeSH
• adaptorové proteiny signální transdukční biosyntéza   MeSH
• adenin analogy a deriváty   farmakologie   MeSH
• chronická lymfatická leukemie farmakoterapie   metabolismus   patologie   MeSH
• forkhead box protein O1 metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• piperidiny farmakologie   MeSH
• pohyb buněk * MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• regulace genové exprese u leukemie * MeSH
• signální transdukce * MeSH
• upregulace * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Spindle cell lipoma, cellular angiofibroma and mammary myofibroblastoma are mesenchymal tumours that have overlapping morphological and immunophenotypic features. Aberrations in chromosome 13q14 have been identified as a recurrent feature. We report a unique case of a 69-year-old woman who metachronously developed all three tumours. She developed a peri-urethral and a recurrent peri-vaginal cellular angiofibroma at age 54 and 57, respectively, a spindle cell lipoma at age 62 and a mammary myofibroblastoma at age 69. Dual-colour interphase fluorescent in situ hybridisation (FISH) revealed losses of RB1 and FOXO1 (13q14LOH [loss of heterozygosity]) within neoplastic cells. There was also loss of retinoblastoma (Rb) protein expression. To our knowledge, this is the first report of these three tumours arising in the same patient. The genetic link between these tumours supports the hypothesis that they may arise from the same progenitor cells. However, further research is required to elucidate the precise pathogenetic link.

• MeSH
• angiofibrom genetika   patologie   MeSH
• fenotyp MeSH
• forkhead box protein O1 genetika   MeSH
• genetická predispozice k nemoci MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• lidské chromozomy, pár 14 * MeSH
• lipom genetika   patologie   MeSH
• nádorové biomarkery genetika   MeSH
• nádory močové trubice genetika   patologie   MeSH
• nádory prsu genetika   patologie   MeSH
• nádory vaginy genetika   patologie   MeSH
• nádory ze svalové tkáně genetika   patologie   MeSH
• sekundární malignity genetika   patologie   MeSH
• senioři MeSH
• ubikvitinligasy genetika   MeSH
• vazebné proteiny retinoblastomu genetika   MeSH
• ztráta heterozygozity * MeSH
• Check Tag
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

FOXO transcription factors regulate cellular homeostasis, longevity and response to stress. FOXO1 (also known as FKHR) is a key regulator of hepatic glucose production and lipid metabolism, and its specific inhibition may have beneficial effects on diabetic hyperglycemia by reducing hepatic glucose production. Moreover, all FOXO proteins are considered potential drug targets for drug resistance prevention in cancer therapy. However, the development of specific FOXO inhibitors requires a detailed understanding of structural differences between individual FOXO DNA-binding domains. The high-resolution structure of the DNA-binding domain of FOXO1 reported in this study and its comparison with structures of other FOXO proteins revealed differences in both their conformation and flexibility. These differences are encoded by variations in protein sequences and account for the distinct functions of FOXO proteins. In particular, the positions of the helices H1, H2 and H3, whose interface form the hydrophobic core of the Forkhead domain, and the interactions between hydrophobic residues located on the interface between the N-terminal segment, the H2-H3 loop, and the recognition helix H3 differ among apo FOXO1, FOXO3 and FOXO4 proteins. Therefore, the availability of apo structures of DNA-binding domains of all three major FOXO proteins will support the development of FOXO-type-specific inhibitors.

• MeSH
• forkhead box protein O1 chemie   genetika   metabolismus   MeSH
• forkhead transkripční faktory chemie   genetika   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• molekulární modely MeSH
• myši MeSH
• protein FOXO3 chemie   genetika   metabolismus   MeSH
• proteinové domény MeSH
• sekundární struktura proteinů MeSH
• sekvenční analýza proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized type of sarcoma arising exclusively in the sinonasal tract displaying unique clinical course, histopathology, and genetics. Due to its rarity, only case series and case reports are available. In order to provide an overview of the current understanding of this disease, we present a comprehensive review of the literature and present three previously unreported cases of BSNS. A total of 55 genetically characterized and 41 cases without molecular data were identified in the literature. Two-thirds of patients were female and the peak incidence was in the fifth decade. Fatal outcome was rare (two cases with intracranial extension) and local recurrence occurred in 31.6%, all occurring within 5 years after initial treatment. Histologically, BSNS is highly cellular in the majority of cases and composed of fascicles of spindle cells, with entrapped hyperplastic surface epithelium being a frequent finding. The immunohistochemical profile is characteristic due to the biphasic nature of this lesion, with shared features of both myogenic and neural origin. Rhabdomyoblastic differentiation is apparent in a subset of cases. The most common genetic event is the PAX3-MAML3 fusion (58.6%) but isolated PAX3 rearrangement (19.2%), absence of rearrangements (9.1%), PAX3-FOXO1 (8.1%), PAX3-NCOA1 (4%), and isolated MAML3 rearrangement (2%) have also been reported. In conclusion, the recognition of BSNS is crucial due to its relatively indolent clinical course. A selected immunohistochemical panel and/or molecular confirmation can be used to aid in appropriate diagnosis and consequently in prognostication and to avoid overtreatment with chemotherapy regimens used in its mimics.

• MeSH
• DNA vazebné proteiny genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• forkhead box protein O1 genetika   MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny genetika   MeSH
• genová přestavba MeSH
• imunohistochemie MeSH
• jaderné proteiny genetika   MeSH
• koaktivátor 1 jaderných receptorů genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory vedlejších dutin nosních diagnóza   genetika   patologie   MeSH
• prognóza MeSH
• sarkom diagnóza   genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transkripční faktor PAX3 genetika   MeSH
• transkripční faktory paired box genetika   MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society.

• MeSH
• alveolární rhabdomyosarkom farmakoterapie   epidemiologie   genetika   patologie   MeSH
• dítě MeSH
• dospělí MeSH
• forkhead box protein O1 genetika   MeSH
• kojenec MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   epidemiologie   genetika   patologie   MeSH
• lymfatické metastázy MeSH
• lymfatické uzliny účinky léků   patologie   chirurgie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• pediatrie MeSH
• předškolní dítě MeSH
• přežití bez známek nemoci MeSH
• prognóza * MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   MeSH
• rizikové faktory MeSH
• staging nádorů MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH