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Emerging mechanism and therapeutic potential of neurofibromatosis type 1-related nerve system tumor: Advancing insights into tumor development.

Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 gene, which increases susceptibility to various nervous system tumors, including plexiform neurofibromas, malignant peripheral nerve sheath tumors, and optic pathway gliomas. Recent research has shown that these tumors are intricately connected to the complex, dynamic interactions within neurons, culminating in neuronal signaling that fosters tumor growth. These interactions offer crucial insights into the molecular mechanisms underpinning tumor development, as well as broader implications for therapeutic

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… Overview of Key Characteristics and Treatment Approaches for NF1-Tumors a Neurofibromatosis type 1. b Plexiform neurofibromas. c Peripheral nervous system. d Loss of heterozygosity. e Schwann cell precursors. f Malignant peripheral nerve sheath tumors. g Optic pathway gliomas. h Central nervous system … The predominant cell population was identified as PLP+ cells, with Krox20+ and Dhh+ cells also present within this group. 65 These cells undergo loss of heterozygosity in the nerve root, subsequently migrating to the dorsal root ganglia and peripheral nerves to form PNF. 64 , 66 These findings have been …

Hypophosphatasia.

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5'-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births

TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a comprehensive overview of targeted approaches.

TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represent a biologically and clinically distinct subset of myeloid malignancies characterized by poor prognosis, resistance to standard therapies, and high rates of relapse. TP53 mutations, particularly biallelic are frequently associated with complex karyotypes and confer profound chemoresistance. Although hypomethylating agents and venetoclax-based combinations provide modest benefit, durable remissions remain rare. Novel therapeutic strategies targeting mutant p53, restoring wild-type function, or exploiting synth

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… It has been recognized that biallelic or “multihit” involvement with multiple mutations or loss of heterozygosity is seen in 44% of MDS patients with TP53 mutations ( 48 ). Conversely, in low-risk MDS, about 20% of patients harbor monoallelic mutations alongside 5q deletion. … Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. …

Diagnostic test accuracy and cost-effectiveness of tests for codeletion of chromosomal arms 1p and 19q in people with glioma.

BACKGROUND: Complete deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q codeletion … tests in use are fluorescent in situ hybridisation (FISH) and polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) assays (also known as PCR-based short tandem repeat or microsatellite analysis). Many other tests are available. None of the tests is perfect, although PCR-based LOH is expected to have very high sensitivity. OBJECTIVES: To estimate the sensi …

Proteasome inhibition paradoxically degrades gain-of-function mutant p53 R273H in NSCLC and could have therapeutic implications.

Lung cancer is the leading cause of cancer mortality. Despite therapeutic advances in recent years, new treatment strategies are needed to improve outcomes of lung cancer patients. Mutant p53 is prevalent in lung cancers and drives several hallmarks of cancer through a gain-of-function oncogenic program, and often predicts a poorer prognosis. The oncogenicity of mutant p53 is related to its stability and accumulation in cells by evading degradation by the proteasome. Therefore, destabilization of mutant p53 has been sought as a therapeutic strategy, but so far without clinical success. In this

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… These arise from missense mutations in TP53 and are characterized by loss of heterozygosity and unusual protein stability, the mechanisms of which are not fully understood. … Nature . ( 2015 ) 523 : 352–6 . doi: 10.1038/nature14430 PMC4506213 26009011 6 Alexandrova EM Mirza SA Xu S Schulz-Heddergott R Marchenko ND Moll UM . p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo . …

Keyword Index for Volume 90

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New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes.

Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies (BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, C

Lymphoma in Border Collies: Genome-Wide Association and Pedigree Analysis.

There has been considerable interest in studying cancer in dogs and its potential as a model system for humans. One area of research has been the search for genetic risk variants in canine lymphoma, which is amongst the most common canine cancers. Previous studies have focused on a limited number of breeds, but none have included Border Collies. The aims of this study were to identify relationships between Border Collie lymphoma cases through an extensive pedigree investigation and to utilise relationship information to conduct genome-wide association study (GWAS) analyses to identify risk reg

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance.

We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three rep

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… (Gln166=/*)—confirmed in parathyroid and pancreas but not in thymus tumors Somatic second-hit mutation in parathyroid: loss of heterozygosity Somatic second-hit mutation in the thymus tumor: MEN1 pathogenic variant in intron 4, c.784-9G>A | Multiple pancreatic NETs PHP Thymus NET Chavoshi 2022 [ 119 … (Gln166=/*) in parathyroid and pancreas NETs but not in thymus NETs associated with a somatic second-hit mutation in parathyroid NETs (loss of heterozygosity) and thymus NETs, respectively ( MEN1 pathogenic variant in intron 4, c.784-9G>A) [ 73 ]. …

Понимание и решение проблемы сопротивления иммуномодуляционным соединениям IMID в множестве миеломы.

Лекарственные средства иммуномодулирования (ИМИД), включая линалидомид и помалидомид в сочетании с протеаозными ингибиторами, дексаметазоном и антиCD38 моноклональными антителами, играют центральную роль в лечении множественной миеломы (ММ) на новых диагностированных и рецидивированных этапах. Эти методы лечения значительно улучшили результаты лечения пациентов во всем мире, в результате чего IMID стали одной из опор MM-терапии. В настоящее время разрабатывается новое поколение более мощных соединений, называемых лигами-модуляторами цереблиона Е3 (CELMODs), которые могут заменить старые IMID.

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… of heterozygosity monocyte chemoattractant protein‐1/2 myeloid‐derived suppressor cell Mitogen‐Activated Protein Kinase Kinase/Extracellular Signal‐Regulated Kinase mezigdomide monoclonal gammopathy of undetermined significance MHC class I polypeptide‐related sequence A macrophage inflammatory … In the Iberdomide phase 1 study, Amatangelo et al . reported that among 81 late line RRMM patients, CRBN exon 10 splicing was detected in 15%, loss of heterozygosity (LOH) at the CRBN locus in 14%, and CRBN mutations in 6%, highlighting the prevalence of CRBN alterations in RRMM. …

Nm23-H1 inhibits lung cancer bone-specific metastasis by upregulating miR-660-5p targeted SMARCA5.

BackgroundNm23-H1 gene has been found to be an inhibitor of tumor metastasis in lung cancer. MicroRNAs (miRNAs) play key roles in tumor metastasis through multiple signaling pathways. This study explored whether the nm23-H1 gene could inhibit invasion and metastasis of lung cancer cells by regulating miRNA-660-5p targets.MethodsQuantitative real-time PCR (qRT-PCR) and western blots were used to measure the expression of nm23-H1 and miR-660-5p of various human lung cancer cell lines. Cell counting kit-8 (CCK-8), wound-healing and transwell assay were carried out to assess cell proliferation, mi

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… of heterozygosity (LOH) is frequently observed in hepatocellular carcinomas. 22 , 23 Furthermore, studies indicate that SMARCA5 expression is dysregulated in many human malignant tumors, such as gastric cancer, breast cancer, prostate cancer, and acute leukemia. 24 , 25 , 26 , 27 Also, SMARCA5 gene … Buetow KH, Murray JC, Israel JL et al Loss of heterozygosity suggests tumor suppressor gene responsible for primary hepatocellular carcinoma. Proc Natl Acad Sci U S A 1989; 86 (22): 8852–6. 24. Gigek CO, Lisboa LC, Leal MF et al SMARCA5 methylation and expression in gastric cancer. …

Comprehensive molecular profiling of 718 Multiple Myelomas reveals significant differences in mutation frequencies between African and European descent cases.

Multiple Myeloma (MM) is a plasma cell malignancy with significantly greater incidence and mortality rates among African Americans (AA) compared to Caucasians (CA). The overall goal of this study is to elucidate differences in molecular alterations in MM as a function of self-reported race and genetic ancestry. Our study utilized somatic whole exome, RNA-sequencing, and correlated clinical data from 718 MM patients from the Multiple Myeloma Research Foundation CoMMpass study Interim Analysis 9. Somatic mutational analyses based upon self-reported race corrected for ancestry revealed significan

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… Wildtype (both TP53 alleles are normal); Mono-Allelic (somatic mutation or copy loss event); Bi-Allelic (somatic TP53 event in both alleles); LOH (loss of heterozygosity only), Mutation (somatic mutation only); LOH+Mutation (combined loss of heterozygosity and mutations) TP53 Aberration | African-American …

Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours.

Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overex

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… In multiple myeloma, loss of heterozygosity (LOH) at 16q, the genomic location of the CYLD gene, is an indicator of poor prognosis and is associated with reduced overall survival ( Jenner et al. , 2007 ). … Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms. Genes Chromosomes Cancer. 2008;47:697–711. doi: 10.1002/gcc.20575. …

Сексуальная последовательность показывает низкочастотные и редкие варианты воздействия на подверженность множественным склерозам в турецких семьях.

Множественный склероз (MS) характеризуется как болезнь центральной нервной системы с иммунной помощью, которая характеризуется хроническим воспалением, обезвоживанием и прогрессивным нейродегенерацией. В этом исследовании мы проанализировали вклад низкочастотных и редких генетических вариантов в подверженность MS в рамках одной из крупнейших на сегодняшний день семейных групп MS, в состав которых входят 215 человек из 59 турецких семей с множественными MS. На всех образцах, включая затронутых и не затронутых членов, была проведена целая последовательность экзотических операций, за которой посл

KRAS mutation in secondary malignant histiocytosis arising from low grade follicular lymphoma.

BackgroundTransformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during t

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… Although copy number alterations were not covered in this assay, analysis of allele frequency of commonly occurring SNVs can be a useful indicator of loss of heterozygosity (LOH). … Variants demonstrate a loss of heterozygosity during transformation from follicular lymphoma to Langerhans cell sarcoma. (DOCX 16 kb) Additional file 4: Table S4. Variants identified in Langerhans cell sarcoma. …

Case Report: Application of ex-vivo drug sensitivity testing to identify personalized treatment options for an adolescent with diffuse midline glioma.

Diffuse midline glioma (DMG) is a pediatric brain cancer that has a dismal prognosis with limited treatment options. We present the treatment course and outcome of an adolescent male diagnosed with a thalamic DMG carrying a histone H3.3 K27M (H3K27M) alteration. Tumor biopsies were taken at diagnosis for histological analysis, molecular profiling, and ex vivo drug sensitivity testing (DST). Seven months after diagnosis, the patient had recurrent/progressive disease after radiotherapy and an ineffective molecular-guided therapy based on tumor molecular profiling. The patient then started a nove

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… Histological staining and molecular analysis of the biopsies revealed the presence of the H3F3A K27M mutation along with mutations in TP53 (with accompanying loss of heterozygosity), PIK3CA , and a SMARCE1 mutation that was sub clonal ( Table 1 ). … For TP53 , there was an accompanying loss of the other allele due to copy-neutral loss of heterozygosity of chromosome 17. “*” indicates that a stop codon was produced by the mutation leading to truncation of the protein. …

State of the Art of Pharmacological Activators of p53 in Ocular Malignancies.

The pivotal role of p53 in the regulation of a vast array of cellular functions has been the subject of extensive research. The biological activity of p53 is not strictly limited to cell cycle arrest but also includes the regulation of homeostasis, DNA repair, apoptosis, and senescence. Thus, mutations in the p53 gene with loss of function represent one of the major mechanisms for cancer development. As expected, due to its key role, p53 is expressed throughout the human body including the eye. Specifically, altered p53 signaling pathways have been implicated in the development of conjunctival

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… In a study by Spandidos et al., 60% of pterygia exhibited several DNA mutations including loss of heterozygosity and microsatellite instability, which result in alterations of the DNA repair pathways [ 152 ]. … Loss of heterozygosity and p53 expression in Pterygium Cancer Lett. 2004 206 77 83 10.1016/j.canlet.2003.10.026 15019163 151. Tsai Y.Y. Cheng Y.W. Lee H. Tsai F.J. Tseng S.H. Chang K.C. P53 gene mutation spectrum and the relationship between gene mutation and protein levels in pterygium Mol. …

Treatment-Associated Acute Lymphoblastic Leukemia Following Autologous Hematopoietic Stem Cell Transplant and Lenalidomide Maintenance in Patients With Multiple Myeloma.

Secondary malignancies including leukemia are an increasing concern in patients with prior primary malignancies treated with alkylating agents or topoisomerase II inhibitors. These can also be referred to as therapy-related leukemia. Therapy-related leukemia most commonly results in myelodysplastic syndrome or acute myeloid leukemia. The alkylating agent can cause chromosomal aberrations typically manifest as deletions in chromosome 11 or loss of part of complete loss of chromosomes 5 and 7. Conversely, acute lymphoblastic leukemia (ALL) has been described following maintenance therapy with im

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… Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. …

Keyword Index for Volume 95

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A Clinical Genetics-Driven Dual Diagnosis of Prader-Willi Syndrome Due to Mosaic Maternal UPD(15) and NOTCH3-Related CADASIL.

Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader-Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis. He presen

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… SNP-array is especially useful when mosaic UPD produces a copy-neutral loss of heterozygosity pattern, while MS-MLPA can provide complementary methylation and dosage information and may help estimate mosaicism. …