Cancer Genet
· 2025 Jun · PMID 40315635
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PTPN3 regulates cellular signaling and is dysregulated in cancer. There has been less research about the oncogenic impact of PTPN3 in breast cancer patients. This study analyzed PTPN3 mRNA levels and their prognostic sig...PTPN3 regulates cellular signaling and is dysregulated in cancer. There has been less research about the oncogenic impact of PTPN3 in breast cancer patients. This study analyzed PTPN3 mRNA levels and their prognostic significance in breast cancer using TCGA datasets. qRT-PCR was used to assess PTPN3 expression in formalin-fixed, paraffin-embedded Indian breast cancer patient samples (tumor-74, control-36). PTPN3 protein levels (ER-positive 15; ER-negative: 15; distant normal breast tissues: 20) were also immunohistochemically assessed using the H-score method. The biomarker potential was examined using a receiver operating characteristic (ROC) analysis. Docking and molecular dynamics (MD) simulations were used to find PTPN3 inhibitors (PDB ID: 2B49) from 892 FDA-approved natural chemicals in the ZINC database. PTPN3 mRNA and protein expression were significantly higher in breast cancers and associated with clinicopathological variables such as age, ER status, tumor stage, grade, Ki-67 index, menopause, and lymph node metastasis (p < 0.05). ROC analysis revealed an AUC of 0.7654, indicating PTPN3's biomarker potential. Docking yielded three high-affinity inhibitors: Cyclocort (ZINC000003977777), Toposar (ZINC000003938684), and Tetracycline (ZINC000084441937), with binding energies of -9.3, -8.73, and -8.66 kcal/mol, respectively. MD simulations confirmed stable connections via hydrogen bonds and hydrophobic interactions under minimal constraints. In conclusion, PTPN3 overexpression supports its role as a prognostic biomarker, and Cyclocort, Toposar, and Tetracycline need further confirmation as potential PTPN3 inhibitors.
He D, Lv Q, Li B
… +4 more, Xu M, Jiang D, Tang Z, Liu Y
Cancer Genet
· 2025 Jun · PMID 40250265
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Cervical squamous intraepithelial lesions are precancerous lesions caused by high-risk subtypes of human papillomavirus (HPV). The development and prognosis of these lesions may be impacted by host genetics. Sanger seque...Cervical squamous intraepithelial lesions are precancerous lesions caused by high-risk subtypes of human papillomavirus (HPV). The development and prognosis of these lesions may be impacted by host genetics. Sanger sequencing was applied to sequence the breast cancer susceptibility gene (BRCA1) exons in exfoliated cervical cells. Fifteen single nucleotide polymorphisms (SNPs) were identified in the entire exon of BRCA1. It was found that there were 8 missense mutations, 1 nonsense mutation, 4 synonymous mutations, and 2 mutations not located in the protein-coding regions. Functional prediction of BRCA1 missense and synonymous mutation sites was performed using PolyPhen-2, ESEFinder3.0, and SIFT online software. The rs39812263 alteration in the BRCA1 gene was found to be significantly different by the sequencing. A significant difference was observed in the alterations of BRCA1 gene rs398122630 between hrHPV and thin- prep cytology test (TCT) groups (p < 0.05), a negative correlation was observed with both hrHPV and TCT. The genotype and allele frequencies of the BRCA1 gene rs398122630 were significantly different from those of the control group (p < 0.05). Rs398122630 may play a protective role in the progression of cervical cancer. This site is a nonsense mutation, which may lead to the premature termination of protein translation. Subsequently, we queried the Gene Expression Omnibus (GEO) and found that the expression of BRCA1 gene RNA gradually increased in cervical normal epithelium, high-grade cervical intraepithelial neoplasia (CIN), and cervical squamous cell carcinoma (CSCC). Lentiviral vectors were used to construct stable cell lines with BRCA1 (breast cancer susceptibility gene 1) knockout and overexpression. The scratch healing rate of HeLa cells with BRCA1 knockout was significantly higher than that of the negative control group (P < 0.05), while the difference in scratch healing rate in the overexpression group was not statistically significant. Compared to the control group, the proportion of cells in the G1 phase increased in the BRCA1 downregulated group (KD1), while the proportion of cells in the G1 phase decreased in the overexpression group (P < 0.05). The percentage of cells in the S phase decreased in the downregulated group compared to the control group (P < 0.05), and the proportion of cells in the G2 phase increased in the overexpression group compared to the control group (P < 0.05), BRCA1 may be involved in the migration and cell cycle of HeLa cells.
Schilter KF, Nie Q, Adams JN
… +11 more, Jagadish R, Acevedo A, Larson A, Vo SA, Domagala BA, Hernandez KM, Douville C, Wang Y, Coe B, Bettegowda C, Reddi HV
Cancer Genet
· 2025 Jun · PMID 40250264
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MGMT promoter methylation status (hypermethylation) is one of the strongest prognostic and predictive biomarkers in glioblastoma (GBM) and is associated with a more favorable response to alkylating chemotherapies such as...MGMT promoter methylation status (hypermethylation) is one of the strongest prognostic and predictive biomarkers in glioblastoma (GBM) and is associated with a more favorable response to alkylating chemotherapies such as Temozolomide (TMZ). Additionally, it is associated with pseudo progression in GBM, a phenomenon in which early radiographic changes after treatment are indicative of possible tumor recurrence though on histological examination it is consistent with treatment effect. Current methods for evaluation of MGMT promoter methylation status are limited to tumor tissue, requiring invasive biopsy or surgery, prompting the need for a liquid biopsy-based assay to expand and manage therapeutic interventions. The Belay Vantage™ assay evaluates MGMT promoter methylation status in cerebrospinal fluid (CSF) of individuals with known or suspected central nervous system tumors using low input DNA. The assay uses quantitative polymerase chain reaction (qPCR) on DNA extracted from CSF after enzymatic conversion and has an analytical sensitivity of 95.5 % and specificity of 100 %.
Fallon P, Boulouta A, Papacharalambous C
… +2 more, Kyriazoglou A, Vlachostergios PJ
Cancer Genet
· 2025 Jun · PMID 40245483
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BACKGROUND: Rib involvement in Ewing sarcoma (ES) is very rare (3-5 %) and may often lead to unique presentations due to mass effect within the thorax. Molecular studies may sometimes offer insights into disease prognosi...BACKGROUND: Rib involvement in Ewing sarcoma (ES) is very rare (3-5 %) and may often lead to unique presentations due to mass effect within the thorax. Molecular studies may sometimes offer insights into disease prognosis and possible targeted treatment approaches. CASE PRESENTATION: Here we present the case of a 39-year-old female who presented with shortness of breath from a massive primary tumor in the right rib and lung. She was diagnosed with ES, which was confirmed by the presence of EWSR1/FLI-1 rearrangement and received multimodal therapy with neoadjuvant VDC-IE (vincristine-doxorubicin-cyclophosphamide, and ifosfamide-etoposide) followed by surgical excision after partial response, and adjuvant chemoradiation. Unfortunately, the patient experienced histologically confirmed local and distant recurrence after several months. NGS of the recurrent tumor revealed a pathogenic PTEN c.640C>T(p.Q214*) nonsense variant with a very high variant allele frequency (VAF) of 82.6 % but negative germline assessment. She received several lines of chemotherapy but only demonstrated a short response to the oral multi-tyrosine kinase inhibitor cabozantinib before eventually passing away. CONCLUSIONS: PTEN mutations in ES, although rare, may result in a higher likelihood of chemotherapy resistance and poor prognosis. Clinical studies targeting specific molecular traits of these tumors, such as PTEN inactivation, could help improve outcomes in selected cases.
Ran Y, Li L, Wang Z
… +8 more, Sun T, Wen C, Zhang Y, Wang S, Jiang S, Zheng J, Yin C, Zhang C
Cancer Genet
· 2025 Jun · PMID 40245482
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BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths globally. The progression of HCC is influenced by a range of intrinsic and extrinsic factors, necessitating further research into...BACKGROUND: Hepatocellular carcinoma (HCC) is a major contributor to cancer-related deaths globally. The progression of HCC is influenced by a range of intrinsic and extrinsic factors, necessitating further research into the molecular mechanisms involved. While Regulator of G-protein Signaling 14 (RGS14) has shown emerging roles in cancer biology, its function in HCC remains poorly characterized. MATERIALS AND METHODS: RGS14 expression and clinical significance were analyzed using TCGA-LIHC, HCCDB, and GEO datasets. Immunofluorescence (IF) staining was employed to validate protein expression. Functional assays, including cell proliferation, migration, invasion, and in vivo xenograft models, were conducted to assess the oncogenic role of RGS14. Bulk-mRNA sequencing was performed using in situ tumor tissues to identify RGS14-regulated pathways. RESULTS: RGS14 was significantly upregulated in HCC tissues and positively associated with poor patient outcomes. In vitro experiments demonstrated that RGS14 enhanced HCC cell proliferation, migration, and invasion, while in vivo studies confirmed its tumor-promoting effects. Mechanistically, RGS14 activated the extracellular matrix (ECM)-receptor interaction pathway to drive HCC progression. CONCLUSION: Our findings suggest that RGS14 could serve as a novel prognostic marker and therapeutic target for HCC, contributing to improved treatment strategies.
Cancer Genet
· 2025 Jun · PMID 40158325
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Previous research indicates that YAP1 mutations may enhance responses to immune checkpoint inhibitors, and this mutation could serve as a novel predictor of response to immunotherapy across various cancers by increasing...Previous research indicates that YAP1 mutations may enhance responses to immune checkpoint inhibitors, and this mutation could serve as a novel predictor of response to immunotherapy across various cancers by increasing mutation counts. The insulin-secreting pancreatic cell line Rin-5F is commonly used in pharmacological and toxicological studies. In the present study, the author has examined mutations in the YAP1 gene using genomic DNA and complementary DNA from Rin-5F cells. No mutations in the YAP1 gene were identified in the current investigation. The status of the YAP1 gene in an insulinoma cell line has not been previously documented. According to previous research, YAP1 mutations may be associated with enhanced responses to immune checkpoint inhibitors. Given that there is no mutation of the YAP1 gene in this insulinoma cell line, it is possible that immune checkpoint inhibitors may have a reduced impact on insulinoma. To address this question, further clinical trials of immune checkpoint inhibitors are needed for neuroendocrine tumors, such as insulinomas.
Narote S, Desai SA, Patel VP
… +3 more, Deshmukh R, Raut N, Dapse S
Cancer Genet
· 2025 Jun · PMID 40154216
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Immunotherapy has become one of the innovative treatments in malignancy as it activates the immune system to find and eliminate malignant cells. The tumor immunology interface has become increasingly intricate, making th...Immunotherapy has become one of the innovative treatments in malignancy as it activates the immune system to find and eliminate malignant cells. The tumor immunology interface has become increasingly intricate, making the identification of new immune targets and signalling pathways on which to base improved therapeutic strategies an ongoing process. This review, we goal to clarify the contacts between cancer and immune system with a focus on immune surveillance as well as immune evasion mechanisms. Comprehensive immunotherapeutic therapies are overviewed with ICI (CTLA-4, PD-1, PD-L1), CAR-T cell therapy, and cancer vaccines whereas, advanced therapies targeting new immune checkpoints are also elucidated including TIM-3, LAG-3, and TIGIT. The JAK/STAT, MAPK and PI3K-AKT-mTOR pathways are reviewed with regards to cancer progression and immunotherapeutic resistance. The dysregulation of these pathways gives hope for the identification of fresh targets for therapy. Genomics, proteomics, immunopeptidomics, single cell mass spectrometry, CRISPR-based functional genomics and bioinformatics are described as essential for immune target identification and for mapping of cancer relevant signaling pathways. This review also considers some emerging issues in the subject area like the tumor heterogeneity, immune-related adverse events (irAEs), and personalized treatment. These barriers are described to facilitate the understanding of ways to overcome them and increase the efficacy of immunotherapies through combination therapies. This means that by developing new knowledge of immunological targets and pathways, immunoprecision medicine for cancer could greatly enhance outcomes.
Zhang Z, Ji Q, Zhang Z
… +6 more, Lyu B, Li P, Zhang L, Chen K, Fang M, Song J
Cancer Genet
· 2025 Jun · PMID 40154215
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BACKGROUND: Melanoma is a complex and often fatal disease, with NRAS being one of the most frequently mutated genes in this type of cancer. Liquid biopsies, specifically tests for circulating tumor DNA (ctDNA), represent...BACKGROUND: Melanoma is a complex and often fatal disease, with NRAS being one of the most frequently mutated genes in this type of cancer. Liquid biopsies, specifically tests for circulating tumor DNA (ctDNA), represent a promising and less invasive approach to diagnosis. This study aims to develop an ultra-sensitive assay for detecting melanoma NRAS mutant ctDNA. METHODS: To detect rare NRAS mutant ctDNA, we developed the NRAS PASEA assay by screening CRISPR-Cas proteins that recognize the PAM sequence 5'-TTN-3'. This method employs CRISPR-Cas proteins to continuously shear wild-type alleles during isothermal amplification, resulting in exponential amplification of mutant alleles to a detectable level by Sanger sequencing. RESULTS: The developed NRAS Q61R/L/K mutation detection method can detect simulated ctDNA samples with mutant allele fractions (MAF) as low as 0.01 % with 30 mins of PASEA treatment. Notably, the NRAS Q61 K mutation was accurately identified by FnCas12a-based NRAS PASEA, even with the nucleotide at the "N" position in the PAM site "TTN." The method successfully detected ctDNA in patients with malignant melanoma. All patients (5/5) from 15 melanoma blood samples with NRAS Q61R (4/4) and NRAS Q61 K (1/1) mutations were accurately identified, with no false positives among patients with wildtype NRAS Q61. CONCLUSION: Detecting ctDNA from peripheral blood samples is highly significant for melanomas in areas where imaging evaluation is challenging. Our assay demonstrated 100 % consistency with tumor tissue NGS, providing a new analytical strategy for companion diagnosis and dynamic assessment of therapeutic efficacy and disease progression in melanoma.
Hodan R, Ritter V, Han S
… +3 more, Narayan S, Satoyoshi M, Kurian AW
Cancer Genet
· 2025 Jun · PMID 40121845
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BACKGROUND: Guidelines recommend germline genetic testing for specific combinations of primary cancers and ages of diagnoses, but do not recommend testing for all patients with multiple primary cancers (MPC). Patients wi...BACKGROUND: Guidelines recommend germline genetic testing for specific combinations of primary cancers and ages of diagnoses, but do not recommend testing for all patients with multiple primary cancers (MPC). Patients with breast cancer are more likely to receive genetic testing. Here, we evaluated whether a first breast cancer was more likely than another first cancer type to prompt testing referral. METHODS: Using Oncoshare, a breast cancer research database of medical records and the California Cancer Registry, we identified female patients with MPC diagnosed January 2000-June 2023 with breast cancer as either the first or second cancer and seen at Stanford Health Care. We analyzed genetic testing rates after first versus second cancer diagnosis and the yield of pathogenic variants (PV). We evaluated the association between the receipt of genetic testing and timing of breast cancer (1st or 2nd), using univariate and multivariable logistic regression adjusted for age at first diagnosis, race/ethnicity, and time between first and second diagnoses. RESULTS: 1,069 patients met eligibility criteria; 75 % were non-Hispanic white, and 73 % had breast as the first cancer. 342 (32 %) patients had testing, of which 113 (33 %) had at least one PV. Patients with first breast cancer had a trend toward higher testing rate, (OR 1.62, 95 % CI 0.9-3.0), p = 0.11. CONCLUSION: Using a breast cancer research database, MPC patients showed a trend toward being more likely to receive genetic testing when breast cancer preceded another cancer. High yield for a germline pathogenic variant suggests that all MPC patients should have cancer genetics risk assessment.
Okamoto T, Mizuta R, Demachi-Okamura A
… +11 more, Muraoka D, Sasaki E, Masago K, Yamaguchi R, Teramukai S, Otani Y, Date I, Tanaka S, Takahashi Y, Hashimoto N, Matsushita H
Cancer Genet
· 2025 Jun · PMID 40121844
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PURPOSE: Few effective immune prognostic models based on the tumor immune microenvironment (TIME) for glioblastoma have been reported. Therefore, this study aimed to construct an immune prognostic model for glioblastoma...PURPOSE: Few effective immune prognostic models based on the tumor immune microenvironment (TIME) for glioblastoma have been reported. Therefore, this study aimed to construct an immune prognostic model for glioblastoma by analyzing enriched biological processes and pathways in tumors. METHODS: A comprehensive single-sample gene set enrichment analysis (ssGSEA) of gene sets from the Molecular Signatures Database was performed using TCGA RNA sequencing data (141 glioblastoma cases). After evaluating gene sets associated with prognosis using univariable Cox regression, gene sets related to biological processes and tumor immunity in gliomas were extracted. Finally, the least absolute shrinkage and selection operator Cox regression refined the gene sets and a nomogram was constructed. The model was validated using CGGA (183 cases) and Aichi Cancer Center (42 cases) datasets. RESULTS: The immune prognostic model consisted of three gene sets related to biological processes (sphingolipids, steroid hormones, and intermediate filaments) and one related to tumor immunity (immunosuppressive chemokine pathways involving tumor-associated microglia and macrophages). Kaplan-Meier curves for the training (TCGA) and validation (CGGA) cohorts showed significantly worse overall survival in the high-risk group compared to the low-risk group (p < 0.001 and p = 0.04, respectively). Furthermore, in silico cytometry revealed a significant increase in macrophages with immunosuppressive properties and T cells with effector functions in the high-risk group (p < 0.01) across all cohorts. CONCLUSION: Construction of an immune prognostic model based on the TIME assessment using ssGSEA could potentially provide valuable insights into the prognosis and immune profiles of patients with glioblastoma and guide treatment strategies.
Masago K, Ishihara H, Kuroda H
… +14 more, Sasaki E, Fujita Y, Fujita S, Horio Y, Sawabe M, Beppu S, Nishikawa D, Terada H, Kishikawa T, Suzuki H, Shibata H, Ogawa T, Hanai N, Matsushita H
Cancer Genet
· 2025 Jun · PMID 40068431
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Human papillomavirus (HPV), particularly strains 16 and 18, contributes to oropharyngeal squamous cell carcinoma (OPSCC), even in non-smokers and non-drinkers. This study investigated gene expression variations in HPV-po...Human papillomavirus (HPV), particularly strains 16 and 18, contributes to oropharyngeal squamous cell carcinoma (OPSCC), even in non-smokers and non-drinkers. This study investigated gene expression variations in HPV-positive OPSCCs according to the virus genotype. An RNA sequencing analysis of 36 p16-positive OPSCC patients revealed distinct expression patterns between tumors with only E6/E7 transcripts (E6E7) and those with additional E5 transcripts (E5-added). The E6E7 group displayed activation of FOS-related pathways and the NF-κB signaling pathway. Notably, the genes associated with tumor growth and cancer antigens differed between the groups. These findings suggest that the presence of HPV E5 might influence the transformation stages and gene expression, potentially affecting patient outcomes. The E5-added group expressed multiple cancer-associated antigens, presenting potential targets for personalized immunotherapy approaches for HPV-positive OPSCC.
Rajoua N, Daunay A, Triki W
… +7 more, Baraket O, Bouchoucha S, Maghrebi H, Mabrouk A, Deleuze JF, How-Kit A, Kharrat M
Cancer Genet
· 2025 Jun · PMID 40064067
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Microsatellite instability (MSI) is an important biomarker in colorectal cancer (CRC), influencing prognosis and treatment decisions. While conventional MSI detection typically relies on the pentaplex panel, newer marker...Microsatellite instability (MSI) is an important biomarker in colorectal cancer (CRC), influencing prognosis and treatment decisions. While conventional MSI detection typically relies on the pentaplex panel, newer markers like HSP110 T17 (HT-17) and CAT-25 may offer simpler, more cost-effective alternatives. This study aimed to assess the effectiveness of HT-17 and CAT-25 for detecting MSI in sporadic CRC and to explore any links between MSI status and clinicopathological features. A total of 96 Tunisian sporadic CRC patients were included, with MSI status evaluated using HT-17, CAT-25, and the refined mononucleotide repeat pentaplex panel through microsatellite genotyping. Clinicopathological data, such as tumor location and age at diagnosis, were also analyzed for associations with MSI. Among the 96 patients, 9 (9.38%) showed MSI, while 87 were microsatellite stable (MSS). HT-17 demonstrated 100% accuracy and sensitivity, matching the pentaplex panel's performance, while CAT-25 showed limited detection ability. MSI status was significantly linked to tumors in the proximal colon and, unexpectedly, to younger patients (<50 years old). HT-17 proved to be a reliable MSI marker in CRC, offering equivalent performance to the pentaplex panel, with the added advantages of simplicity and cost efficiency. The associations between MSI, tumor location, and younger age at diagnosis may provide valuable insights into CRC biology and clinical management. Further studies with larger cohorts are needed to validate HT-17' s clinical potential, with the goal of improving personalized treatment strategies and prognostic accuracy for CRC patients.
Maekawa F, Hayashida M, Takeoka K
… +8 more, Chagi Y, Takahashi R, Kishimori C, Kotani S, Akasaka T, Sakamoto S, Sumiyoshi S, Ohno H
Cancer Genet
· 2025 Jun · PMID 40058168
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A woman in her 80 s presented with generalized lymphadenopathy, bone marrow (BM) involvement, and leukemic manifestation. Lymph node biopsy revealed typical histopathology of mantle cell lymphoma (MCL) and the CD5 and im...A woman in her 80 s presented with generalized lymphadenopathy, bone marrow (BM) involvement, and leukemic manifestation. Lymph node biopsy revealed typical histopathology of mantle cell lymphoma (MCL) and the CD5 and immunoglobulin μδ/λ immunophenotype, with unmutated IGHV. BM was infiltrated with not only MCL but also another B-cell tumor that was CD5 and μδ/κ, being consistent with M proteins in the serum and urine, with mutated IGHV. As the latter lymphoma component carried the MYD88 L265P mutation, this case represented a composite of MCL and lymphoplasmacytic lymphoma. Next-generation sequencing revealed a cryptic insertion of IGK enhancer sequences into the CCND1-major translocation cluster, accounting for CCND1 expression in MCL cells recognized by immunohistochemistry. Composite lymphoma is rare, but a correct diagnosis is required because effective treatments for each component are now available.
You C, Fang Q, Xiao X
… +7 more, Liu Y, Yang W, Qing L, Li Q, Li R, Wang Y, Dong Z
Cancer Genet
· 2025 Jun · PMID 40058167
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BACKGROUND: ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) plays a critical role in multiple cancers; however, its role in bladder cancer (BC) remains largely unexplored. This study investigates the impact of...BACKGROUND: ENPP1 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 1) plays a critical role in multiple cancers; however, its role in bladder cancer (BC) remains largely unexplored. This study investigates the impact of ENPP1 on tumor progression, apoptosis, and the immune microenvironment through bioinformatics and experimental validation. MATERIALS AND METHODS: ENPP1 expression and clinical significance were analyzed using TCGA-BLCA, GEO datasets, and a local clinical cohort of 36 BC patients. Immune infiltration and functional enrichment were assessed using ESTIMATE, CIBERSORT, and clusterProfiler. Single-cell RNA sequencing (scRNA-seq) data examined ENPP1 expression in BC tissues. Stable ENPP1-overexpressing (UMUC3) and ENPP1-knockdown (J82) cell lines were established. Functional assays, including proliferation, migration, and apoptosis marker analysis, were performed. RESULTS: RT-qPCR, Western blotting, and immunohistochemistry confirmed differential ENPP1 expression between BC tissues and adjacent normal tissues. High ENPP1 expression was associated with worse overall survival (OS), advanced T and N stages, and poor pathological grades. Functional assays demonstrated that ENPP1 overexpression enhanced proliferation, migration, and apoptosis resistance, while knockdown suppressed these processes. Mechanistically, ENPP1 overexpression reduced pro-apoptotic markers BAX and Caspase-3 while increasing anti-apoptotic Bcl-2. Immune infiltration analysis revealed a positive correlation between ENPP1 expression and M2 macrophage infiltration, alongside decreased CD8+ T cell infiltration. scRNA-seq identified high ENPP1 expression in cancer-associated fibroblasts and epithelial cells. Drug sensitivity analysis linked elevated ENPP1 expression to resistance against chemotherapies like gemcitabine and cytarabine. CONCLUSION: ENPP1 drives tumor progression, modulates immune infiltration, and contributes to chemotherapy resistance in BC, underscoring its potential as a therapeutic target.
Rothmund-Thomson syndrome (RTS) is a multisystemic tumour-predisposing genodermatosis caused by biallelic pathogenic alterations in the ANAPC1 gene or RECQL4 gene. Herein we describe the clinical and genetic findings in...Rothmund-Thomson syndrome (RTS) is a multisystemic tumour-predisposing genodermatosis caused by biallelic pathogenic alterations in the ANAPC1 gene or RECQL4 gene. Herein we describe the clinical and genetic findings in three individuals with molecularly substantiated RECQL4-related RTS. Based on the disease course of two patients with osteosarcoma, we highlight the critical importance of early diagnosis.
Spinal tumors, although rare, pose significant challenges in diagnosis and treatment due to their complex biological behavior and the variety of tumor types involved. MicroRNAs (miRNAs), small non-coding RNA molecules, h...Spinal tumors, although rare, pose significant challenges in diagnosis and treatment due to their complex biological behavior and the variety of tumor types involved. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as critical regulators of gene expression and play dual roles as oncogenes or tumor suppressors, depending on their target genes. This review comprehensively examines the role of miRNAs in the pathogenesis and progression of common spinal tumors, including ependymoma, astrocytoma, meningioma, and metastasis, based on existing studies using both human and in vitro models. Several miRNAs have been identified as dysregulated in these tumor types, influencing key cellular processes such as proliferation, migration, and apoptosis. The potential of miRNAs as diagnostic, prognostic, and therapeutic biomarkers is explored, highlighting their value in guiding personalized treatment approaches. Although promising, these findings require further validation to fully understand miRNA-mediated mechanisms and translate these insights into clinical applications. MiRNA-targeted therapies offer a promising avenue for improving patient outcomes in spinal tumor management.
Germline pathogenic variants (PVs) in CBL are found in 15 % of juvenile myelomonocytic leukemia (JMML) cases. Here we report three siblings with CBL(NM_005188):c.1111T>C variation presenting a heterogenous JMML clinic an...Germline pathogenic variants (PVs) in CBL are found in 15 % of juvenile myelomonocytic leukemia (JMML) cases. Here we report three siblings with CBL(NM_005188):c.1111T>C variation presenting a heterogenous JMML clinic and outcome. The index case was diagnosed at the age of seven, whereas the younger brother was 10 months old and the youngest was one month old. The hematopoietic stem cell transplantation was successful for the index and the youngest brother with event-free survival, but the middle brother showed severe graft versus host disease. This study shows the heterogeneity of JMML and how the outcome might differ even within the family.
Although testing and treatment of blood malignancies have been standardized, additional unidentified genetic abnormalities often complicate the diagnosis and therapeutic outcome. Thus, improvement of contemporary therapy...Although testing and treatment of blood malignancies have been standardized, additional unidentified genetic abnormalities often complicate the diagnosis and therapeutic outcome. Thus, improvement of contemporary therapy requires further stratification of patients based on detailed genetic information. Here, we describe an extremely rare case of Philadelphia chromosome-like T-cell acute lymphoblastic leukemia (Ph-like T-ALL) with NUP214-ABL1 fusion and presentation of unusually enlarged nuclei in the leukemic cells, which was attributed to tetraploidy. Despite receiving the protocol-guided induction chemotherapy, the patient did not respond favorably. The challenges in treating Ph-like T-ALL with rare genetic abnormalities, highlight the need of further research and personalized medication.
We present a detailed cytogenomic analysis from a patient with suspected acute promyelocytic leukemia (APL), based on morphological and immunophenotypic characteristics. Initial testing with fluorescence in situ hybridiz...We present a detailed cytogenomic analysis from a patient with suspected acute promyelocytic leukemia (APL), based on morphological and immunophenotypic characteristics. Initial testing with fluorescence in situ hybridization (FISH) and chromosome analysis was negative for the canonical PML::RARA and other RARA partners translocations. Polymerase chain reaction (PCR) did not detect PML::RARA transcripts. However, chromosome analysis results revealed loss of 5q and 17p, as well as the presence of double minutes (dmin). To further assess the involvement of other retinoic acid receptor (RAR) partners, such as RARB and RARG, and to elucidate the origin of the dmin, we conducted genome-wide structural variant analysis (gwSVA) using optical genome mapping (OGM) as part of a research and confirmatory follow-up. Using gwSVA, we identified the double minutes to be of MYC origin, with approximately 44 copies. Additionally, gwSVA revealed a loss of TP53, along with polyploidy showing loss of chromosomes 1, 2, 8, 9 (including CDKN2A), 10, 11, 15 and gains of chromosomes 3, 6, and 7 indicating distinct clonal events in a diagnostic and follow up bone marrow. Next generation sequencing (NGS) with an exome-based heme targeted panel identified a Tier I deleterious TP53 single nucleotide variant (p.S241C). The follow-up bone marrow analyzed with gwSVA, four months post-induction therapy, showed a reduction in number of cells exhibiting MYC amplification. This study provides a rare instance of a TP53 positive case with APL-like bone marrow morphology, no RARA rearrangement, and MYC amplification. It further lends evidence towards comprehensive cytogenomic and molecular analyses for accurate risk stratification and subsequent disease tracking.
Desrosiers-Battu LR, Lee JH, Tarasiewicz I
… +17 more, Gilbert AR, Galvan EM, Singh AK, Roy A, Miles G, Reuther J, Muzny DM, Yuan B, Kulkarni S, Eng C, Scollon S, Gessay S, McGuire AL, Parsons DW, Tomlinson GE, Plon SE, Shah S
Meningiomas are the most common primary brain tumors in adults but much less frequent in children. Many subtypes exist, including anaplastic (malignant) meningioma, which accounts for less than 20% of pediatric tumors. M...Meningiomas are the most common primary brain tumors in adults but much less frequent in children. Many subtypes exist, including anaplastic (malignant) meningioma, which accounts for less than 20% of pediatric tumors. Meningiomas can arise in association with cancer predisposition syndromes due to germline variants in genes such as NF2, MEN1 and SMARCE1. This report describes a 6-year-old boy diagnosed with anaplastic meningioma who was treated with surgery and focal radiation therapy. The family consented to participate in the Texas KidsCanSeq clinical genomics study. Analysis of germline and tumor samples detected a single germline finding of a CDKN1B pathogenic frameshift variant associated with Multiple Endocrine Neoplasia Type 4 (MEN4) without somatic loss of the other allele. Tumor analysis revealed a YAP1::MAML2 fusion, which has been previously reported in pediatric meningiomas not associated with NF2. YAP1::MAML2 fusion is a known driver for development of meningioma, but the role of the germline CDKN1B variant in the absence of a tumor second hit is unclear. This case highlights the importance of performing combined tumor and germline molecular genetic analysis of rare tumors to help clarify the risk of development of cancer in patients with rare cancer predisposition syndromes.