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BioRxiv : the Preprint Server For... May 2024Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase...
Cancer mutations can create neomorphic protein-protein interactions to drive aberrant function . As a substrate receptor of the CULLIN3-RBX1 E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma (MB) , the most common embryonal brain tumor in children, and pineoblastoma . These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST . However, their mechanism of action remains unresolved. Here, we elucidate the mechanistic basis by which KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2, the direct neomorphic target of the substrate receptor. Using deep mutational scanning, we systematically map the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy (cryo-EM) analysis of two distinct KBTBD4 cancer mutants bound to LSD1-HDAC1-CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat propeller domains. The interface between HDAC1 and one of the KBTBD4 propellers is stabilized by the MB mutations, which directly insert a bulky side chain into the active site pocket of HDAC1. Our structural and mutational analyses inform how this hotspot E3-neo-substrate interface can be chemically modulated. First, our results unveil a converging shape complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4-HDAC1 interface, the aberrant degradation of CoREST, and the growth of KBTBD4-mutant MB models. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein-protein interactions and pharmacological strategies to modulate their action for therapeutic applications.
PubMed: 38798357
DOI: 10.1101/2024.05.14.593970 -
Problemy Endokrinologii Oct 2023DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a... (Review)
Review
DICER1 syndrome is a rare genetic disorder with the progressive development of malignant and non-malignant diseases in childhood. The cause of this syndrome is a dusfunction of the endoribonuclease DICER, which plays an important role in the processing of microRNAs with subsequent regulation of the control of the expression of oncogenes and tumor suppressor genes. Clinical manifestations of dyseropathies is very different and may include both endocrine manifestations - multinodular goiter, differentiated thyroid cancers, ovarian stromal tumors, pituitary blastoma, and non-endocrine formations - pleuropulmonary blastoma, cystic nephroma, pineoblastoma. The presence of somatic mutations of the DICER1 gene is a resultant stage in the pathogenesis of dyseropathies, determining the further path of oncogenesis. At present, DICER1 syndrome is diagnosed extremely rarely, which leads to late detection of the components of the disease in the patient, late diagnosis of neoplasms, lack of family counseling. Diagnosis at the early stages of the disease, the development of screening programs for the management of these patients allows minimizing the risks of developing more malignant, aggressive forms of the disease.
Topics: Humans; Ribonuclease III; DEAD-box RNA Helicases; Mutation; Female; Thyroid Neoplasms; Goiter, Nodular; Pulmonary Blastoma
PubMed: 38796764
DOI: 10.14341/probl13383 -
BioRxiv : the Preprint Server For... Apr 2024Mutations in the microRNA processing genes and drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we...
Mutations in the microRNA processing genes and drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated or in the developing pineal gland to emulate the pathogenesis of pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. Accordingly, these mice develop pineal tumors marked by loss of microRNAs, including the let-7/miR-98-5p family, and de-repression of microRNA target genes. Pineal tumors driven by loss of or mimic tumors driven by loss, as they exhibit upregulation of S-phase genes and homeobox transcription factors that regulate pineal development. Blocking proliferation of these tumors facilitates expression of pinealocyte maturation markers, with a concomitant reduction in embryonic markers. Select embryonic markers remain elevated, however, as the microRNAs that normally repress these target genes remain absent. One such microRNA target gene is the oncofetal transcription factor , which regulates expression of pro-growth genes, and inhibiting their signaling impairs tumor growth. Thus, we demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
PubMed: 38712047
DOI: 10.1101/2024.04.23.590638 -
Cureus Mar 2024Pineal parenchymal tumors (PPTs) are rare, accounting for less than 0.3% of all primary central nervous system (CNS) tumors. Pineal parenchymal tumors of intermediate...
Pineal parenchymal tumors (PPTs) are rare, accounting for less than 0.3% of all primary central nervous system (CNS) tumors. Pineal parenchymal tumors of intermediate differentiation (PPTID) (WHO grade 2 or 3) show an intermediate prognosis between pineocytoma and pineoblastoma. The clinical course is unknown, and the optimal treatment for PPTID, especially for recurrence, has not been determined. We report a case of PPTID with spinal dissemination over 10 years after treatment and survival for four years. A 56-year-old woman presented with headaches and diplopia. Computerized tomography (CT) and magnetic resonance imaging (MRI) revealed a pineal mass, but leptomeningeal dissemination was not identified on whole-spine MRI. Microsurgical gross total tumor resection (GTR) was performed, and the pathological diagnosis was PPTID (grade 3). In addition, a later study found it to harbor a mutation. She underwent whole-brain radiation therapy with a focal boost. The patient was unable to continue chemotherapy for severe myelosuppression after the first course of treatment. Eleven years after the surgery, she was unable to walk, and a whole-spine MRI revealed multiple masses at C3-4, T4, and cauda equina. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed accumulations of the same lesions. No recurrence was observed in the brain. A biopsy of the caudal portion was performed, and the histopathological findings were the same as those of the initial surgery. Spinal dissemination was refractory to chemotherapy but responded to whole spine radiotherapy with focal boost, and she remained tumor-free for four years. We considered good local control with a combination of GTR and subsequent radiation therapy to contribute to long-term survival. The timing of spinal radiation administration is controversial because of the tendency for late cerebrospinal dissemination. The importance of long-term follow-up of the spine and head is emphasized. In PPTID cases with good local control, withholding spinal radiation until spinal dissemination occurs may become a long-term treatment plan.
PubMed: 38681294
DOI: 10.7759/cureus.57147 -
Frontiers in Oncology 2024Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs...
BACKGROUND
Pure germinomas account for 40% of pineal tumors and are characterized by the lack of appreciable tumor markers, thus requiring a tumor biopsy for diagnosis. MicroRNAs (miRNA) have emerged as potential non-invasive biomarkers for germ cell tumors and may facilitate the non-invasive diagnosis of pure pineal germinomas.
MATERIAL AND METHODS
A retrospective chart review was performed on all patients treated at the Children's Cancer Hospital Egypt diagnosed with a pineal region tumor between June 2013 and March 2021 for whom a research blood sample was available. Plasma samples were profiled for miRNA expression, and DESeq2 was used to compare between pure germinoma and other tumor types. Differentially expressed miRNAs were identified. The area under the curve of the receive;r operating characteristic curve was constructed to evaluate diagnostic performance.
RESULTS
Samples from 39 pediatric patients were available consisting of 12 pure germinomas and 27 pineal region tumors of other pathologies, including pineal origin tumors [ = 17; pineoblastoma ( = 13) and pineal parenchymal tumors of intermediate differentiation ( = 4)] and others [ = 10; low-grade glioma ( = 6) and atypical teratoid rhabdoid tumor ( = 4)]. Using an adjusted -value <0.05, three miRNAs showed differential expression (miR-143-3p, miR-320c, miR-320d; adjusted = 0.0058, = 0.0478, and = 0.0366, respectively) and good discriminatory power between the two groups (AUC 90.7%, < 0.001) with a sensitivity of 25% and a specificity of 100%.
CONCLUSION
Our results suggest that a three-plasma miRNA signature has the potential to non-invasively identify pineal body pure germinomas which may allow selected patients to avoid the potential surgical complications.
PubMed: 38665953
DOI: 10.3389/fonc.2024.1219796 -
Journal of Cancer Research and... Jan 2024Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high...
BACKGROUND
Small round cell tumors (SRCTs) are a group of malignant neoplasms with minimal or no differentiation, characterized by the presence of round cells with high nuclear-cytoplasmic ratio. Although SRCTs can occur in any part of the body, involvement of central nervous system (CNS) is uncommon.
AIM
We aimed to study the clinicopathological spectrum of cranial SRCT diagnosed in our institute over a period of four years (2016-2019).
MATERIAL AND METHODS
A retrospective review of medical records (2016-2019) with a morphological diagnosis of cranial SRCT was made. Both intra-axial and extra-axial tumors were included. A total of 60 cases were retrieved, and the clinical and histopathological features were studied. Special cytochemical staining and immunohistochemistry were performed, where needed.
RESULTS
The mean age at presentation was 18.4 years (range, 1-60 years), with a male-to-female ratio of 2.5:1. The most common site was posterior fossa of brain (n = 28, 47%), followed by dorso-lumbar spine (n = 9, 15%). The most common type of tumor was medulloblastoma (n = 29, 48.3%), followed by Ewing sarcoma (ES)/peripheral primitive neuroectodermal tumor (pPNET) (n = 11, 18.3%), non-Hodgkin lymphoma (NHL) (n = 9, 15%), neuroblastoma (n = 3, 5%), and CNS embryonal tumor, NOS (n = 2, 3.3%). One case each of atypical teratoid rhabdoid tumor (ATRT), rhabdomyosarcoma, pineoblastoma, melanoma, rhabdomyosarcoma, and undifferentiated pleomorphic sarcoma was also documented.
CONCLUSIONS
SRCTs have a variable age of presentation. Their incidence in CNS is low as compared to other organ systems. On light microscopy, the histopathology of these lesions is overlapping, posing a great diagnostic dilemma for the pathologist. The use of ancillary techniques like immunohistochemistry helps in arriving at the correct diagnosis. Treatment strategy and tumor prognosis also vary along the entire spectrum of SRCT, thus making exact characterization essential for proper management.
Topics: Humans; Male; Female; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Tertiary Care Centers; Sarcoma; Rhabdomyosarcoma; Neuroectodermal Tumors, Primitive; Central Nervous System Neoplasms; Neoplasms, Germ Cell and Embryonal; Cerebellar Neoplasms
PubMed: 38554327
DOI: 10.4103/jcrt.jcrt_383_22 -
Brain Pathology (Zurich, Switzerland) May 2024
Topics: Female; Humans; Pineal Gland; Pinealoma; Brain Neoplasms
PubMed: 38527786
DOI: 10.1111/bpa.13258 -
Magyar Onkologia Mar 2024Pineal region tumors account for less than 1% of adult supratentorial tumors. Their treatment requires a multimodality approach. Previously, the treatment of choice was... (Review)
Review
Pineal region tumors account for less than 1% of adult supratentorial tumors. Their treatment requires a multimodality approach. Previously, the treatment of choice was direct surgery, which is associated with high surgical risk. Advances in minimally invasive techniques and onco-radiotherapy offer a safe and multimodal personalized therapy. The aim of our study was to describe the practice of our Institute based on combined endoscopic and radiotherapy techniques. We performed a retrospective clinical study. We processed data from 23 adult patients who underwent endoscopic third ventricle fenestration and pineal tumor biopsy between 2014 and 2023. Descriptive statistics, t-test, Fisher's exact test and Kaplan-Meier analysis were performed. Clinical improvement with endoscopic intervention was achieved in 78.3% of cases. Significant increase in preoperative performance status was observed in the postoperative period (p=2.755e-5), and radiotherapy resulted in regression or stable disease. Our results suggest a safe treatment with good clinical outcome and an excellent alternative to direct surgery.
Topics: Adult; Humans; Brain Neoplasms; Combined Modality Therapy; Pineal Gland; Pinealoma; Retrospective Studies
PubMed: 38484373
DOI: No ID Found -
BMC Pediatrics Mar 2024Germline mutations of NSD1 are associated with Sotos syndrome, characterized by distinctive facial features, overgrowth, and developmental delay. Approximately 3% of...
Germline mutations of NSD1 are associated with Sotos syndrome, characterized by distinctive facial features, overgrowth, and developmental delay. Approximately 3% of individuals with Sotos syndrome develop tumors. In this study, we describe an infant in pineoblastoma with facial anomalies, learning disability and mild autism at 1 years diagnosed as Sotos syndrome owing to carrying a novel mutation de novo germline NSD1 likely pathogenic variant. This patient expands both the mutation and phenotype spectrum of the Sotos Syndrome and provides new clinical insights into the potential mechanism of underlying pinealoblastoma pathology.
Topics: Infant; Humans; Sotos Syndrome; Histone-Lysine N-Methyltransferase; Histone Methyltransferases; Germ-Line Mutation; Pinealoma; Mutation; Brain Neoplasms; Pineal Gland
PubMed: 38459438
DOI: 10.1186/s12887-024-04636-y