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Nature Genetics Dec 2023Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes....
Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.
Topics: Humans; DNA, Circular; Medulloblastoma; Retrospective Studies; Neoplasms; Oncogenes; Cerebellar Neoplasms
PubMed: 37945900
DOI: 10.1038/s41588-023-01551-3 -
Nucleic Acids Research Mar 2024Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic....
Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
Topics: Humans; AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase; Demethylation; DNA Methylation; Histones; Melanoma; Promyelocytic Leukemia Protein; RNA; Transcription Factors; Antigens, Nuclear; Autoantigens; Eye Neoplasms
PubMed: 38118002
DOI: 10.1093/nar/gkad1193 -
Endocrine Journal Nov 2023Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to...
Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.
Topics: Humans; Insulin-Like Growth Factor I; Acromegaly; Receptor, IGF Type 1; Thyroid Diseases; Graves Ophthalmopathy; Goiter; Receptors, Thyrotropin; Human Growth Hormone; Growth Hormone; Thyroid Neoplasms
PubMed: 37880078
DOI: 10.1507/endocrj.EJ23-0356 -
Ugeskrift For Laeger Dec 2023In this case report, two patients were initially presented with orbital symptoms due to undiagnosed sinonasal disease. An eight-year-old girl was suspected of preseptal...
In this case report, two patients were initially presented with orbital symptoms due to undiagnosed sinonasal disease. An eight-year-old girl was suspected of preseptal cellulitis due to swelling and redness around the right eye for a month. MRI of the orbit showed a change in the orbit suspected to be a tumour. Regression in symptoms was seen after three months and a mucocele was suspected. The other patient was a 57-year-old woman suspected of left-side acute dacryocystitis with a palpable mass above the medial canthus for a month. MRI was performed due to atypical presentation and showed tumour changes originating from the ethmoid sinus.
Topics: Female; Humans; Middle Aged; Child; Orbit; Head; Neoplasms
PubMed: 38105733
DOI: No ID Found -
Medical Sciences (Basel, Switzerland) Nov 2023Although liposarcoma is the most prevalent soft tissue sarcoma in adults, head and neck liposarcomas are rare and account for less than 5% of all liposarcomas. The...
Although liposarcoma is the most prevalent soft tissue sarcoma in adults, head and neck liposarcomas are rare and account for less than 5% of all liposarcomas. The primary orbital location is even more exceptional, with fewer than 100 cases documented in the medical literature. Given the scarcity of cases of orbital liposarcoma and the limited familiarity of physicians and pathologists with this pathology, there is an increased risk of non-diagnosis or misdiagnosis, which may lead to inappropriate patient management. To address these challenges, we present a case of primary orbital myxoid liposarcoma and subsequently discuss the primary findings of this case based on the evidence documented in the medical literature. This comprehensive text is designed to serve as a valuable resource for healthcare professionals and pathologists, with the goal of promoting both clinical suspicion and accurate diagnosis and treatment of this rare condition in future cases.
Topics: Adult; Humans; Liposarcoma, Myxoid; Soft Tissue Neoplasms; Neck
PubMed: 37987327
DOI: 10.3390/medsci11040072