Cancer Genetics[JOURNAL]
Sun
200 papers
Two MLN-TK patients with ETV::ABL1 fusions mediated by different mechanisms with false negative FISH results resolved with RNA fusion analysis.
Maher P, Jang T, Vega RR … +8 more , Miatech J, Mora GB, Quan WJR, Prince R, Chaffin J, Yang L, Starostik P, Burnside RD
Cancer Genet · 2025 Sep · PMID 40618562 · Publisher ↗
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (MLN-TK) is a newly added entity in the World Health Organization (WHO) 5 Edition, and within this category, ETV6::ABL1 gene fusions are the most c...
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusions (MLN-TK) is a newly added entity in the World Health Organization (WHO) 5 Edition, and within this category, ETV6::ABL1 gene fusions are the most commonly reported in the literature. While patients may respond favorably to tyrosine kinase inhibitor (TKI) therapy, prognosis is generally less favorable than for BCR::ABL1-positive chronic myelogenous leukemia (CML), also treated with tyrosine kinase inhibitor therapy (TKIs). We report two patients diagnosed with MLN-TK, both of whom were positive for ETV6::ABL1 gene fusions, albeit by different mechanisms but with the same breakpoints. Importantly, one of our subjects also demonstrated BCR::ABL1 fusion subclonally to the ETV6::ABL1 fusion positive clone. This study emphasizes the importance of resolving false negative and/or discrepant fluorescence in situ hybridization (FISH) results using alternative methods, such as RNA fusion analysis, to aid in the diagnosis of MLN-TK.
TRIM29 promotes glioblastoma progression via ubiquitinating NEFL and activating the PI3K/AKT signaling pathway.
Liu Y, He Q, Zhu L … +6 more , Zhong M, Zhuang H, Zhao N, Cai Y, Cheng C, Shao J
Cancer Genet · 2025 Sep · PMID 40617179 · Publisher ↗
Tripartite motif-containing protein 29 (TRIM29) is a regulator of tumor progression across multiple cancer types. However, its functional significance in glioblastoma (GBM) remains poorly defined. In this study, we inves...
Tripartite motif-containing protein 29 (TRIM29) is a regulator of tumor progression across multiple cancer types. However, its functional significance in glioblastoma (GBM) remains poorly defined. In this study, we investigated the biological roles of TRIM29 in GBM and elucidated its underlying molecular mechanisms. Clinically, TRIM29 expression was significantly upregulated in glioma tissues compared to adjacent normal brain tissues, and elevated TRIM29 levels correlated with unfavorable prognosis in GBM patients. Functionally, both in vitro (GBM cell lines) and in vivo (a mouse xenograft model) experiments demonstrated that TRIM29 overexpression robustly enhanced GBM cell proliferation, migration, and invasive capacity. Mechanistically, TRIM29 directly interacted with neurofilament light polypeptide (NEFL), triggering K48-linked polyubiquitination and subsequent proteasomal degradation of NEFL[1]. This ubiquitination-dependent NEFL downregulation led to constitutive activation of the PI3K/AKT signaling pathway. Our findings uncover a novel TRIM29-NEFL-PI3K/AKT axis that drives glioblastoma malignancy, highlighting the therapeutic potential of targeting this pathway for GBM treatment.
Evaluating the consistency of SMARCB1 variant classification and assertions of genotype-phenotype relationships in ClinVar.
Satish S, Bone M, Ritter D … +1 more , Plon SE
Cancer Genet · 2025 Sep · PMID 40617178 · Full text
Pathogenic SMARCB1 variants are associated with multiple Mendelian syndromes: Schwannomatosis (SM), Rhabdoid Tumour Predisposition Syndrome (RTPS1), and/or Coffin-Siris Syndrome (CSS). Although some data suggests genotyp...
Pathogenic SMARCB1 variants are associated with multiple Mendelian syndromes: Schwannomatosis (SM), Rhabdoid Tumour Predisposition Syndrome (RTPS1), and/or Coffin-Siris Syndrome (CSS). Although some data suggests genotype/phenotype relationships based on mutation type and location, this is not used consistently potentially due to inconsistent or absent phenotypic data. We used ClinVar, the largest public platform of variant classifications, to evaluate variant-specific data from clinical laboratories and cited publications to assess reporting consistency and genotype-phenotype relationships. When available, we extracted the mutation type, HGVS nomenclature, submitters, publications, and disease conditions. We compared the disease assertions made by laboratory submissions with those made in cited publications. Across 59 SMARCB1 pathogenic variants, we identified 91 laboratory submissions (38 single and 20 multiple laboratories) and 40 cited articles. Of 91 submissions, 40 did not provide any disease assertion. Nonsense RTPS1 variants (n = 23) were mostly located in exon 2, with some in exons 1, 4 and 5, and other variant types were limited to frameshifts and large deletions/duplications. SM variants (n = 10) were found throughout SMARCB1 with diverse variant types. CSS variants (n = 6) were single amino-acid deletions, missense and frameshift variants limited to exons 8 and 9. Although ClinVar is a rich source of variant data and extensively used during variant classification, the frequent absence of disease assertions and inconsistent reporting impedes implementation of clear genotype-phenotype relationships for SMARCB1. Given the significant clinical impact of these diagnoses a more standardized way of reporting pathogenic variants for diseases associated with multiple Mendelian disorders is needed.
GPX4 in triple-negative breast cancer: A key regulator of ferroptosis and therapeutic target.
Baskar G
Cancer Genet · 2025 Sep · PMID 40609246 · Publisher ↗
Breast cancer is the most prevalent cancer among women globally. Triple-negative breast cancer (TNBC) is an exceptionally aggressive and challenging kind of breast cancer to manage. Triple-negative breast cancer (TNBC) l...
Breast cancer is the most prevalent cancer among women globally. Triple-negative breast cancer (TNBC) is an exceptionally aggressive and challenging kind of breast cancer to manage. Triple-negative breast cancer (TNBC) lacks oestrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). As a result, there are no effective targeted therapies for it, and it doesn't respond well to standard treatment. Platinum-based treatments and neoadjuvant chemotherapy have shown promise, but the outlook is still not good. Ferroptosis, a type of regulated cell death that depends on iron, is a new way to treat diseases. Ferroptosis inducers like erastin may help make TNBC cells more sensitive to treatment, but they are still hard to deliver because they are toxic and don't dissolve well. Nanotechnology and drug delivery systems, especially exosome-based carriers, are promising ways to get around these problems. Exosomes are a new way to deliver drugs that cause ferroptosis because they are biocompatible and can target specific cells. This is a very interesting area for developing new treatments for TNBC.
Assessing germline mutational profile and its clinicopathological associations in Triple Negative Breast Cancer.
John J, Bapat A, Gahlaut S … +20 more , Luke N, Kumar R, Thakur Y, Mathew C, Konnur A, Namewar N, Reddy R, Nagarkar S, Nare S, Thomas G, Busheri L, Reddy A, Kelkar D, Dixit S, Deshmukh C, Ul Mannan A, Sabarinathan R, Radhakrishna S, Mishra R, Koppiker CB
Cancer Genet · 2025 Sep · PMID 40578183 · Publisher ↗
BACKGROUND: Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25 %) in India remains a challenge in clinical management. Ass...
BACKGROUND: Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC). The high TNBC prevalence (>25 %) in India remains a challenge in clinical management. Association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. These studies are, however, predominantly representative of western population. Therefore, we investigated germline profiles of multi-institutional cohort of TNBC patients in India METHODS: Multigene NGS (next-generation sequencing) panel testing of Triple Negative Breast Cancer patients was conducted. All patients were offered pre-test and post-test counseling. RESULTS: In our study cohort of 192 TNBC patients, median age at diagnosis was 47 years (23-78). Germline pathogenic mutations were identified in 28.6 % cases. Of the 58 pathogenic mutations identified, BRCA1 accounted for 72.4 % and BRCA2 for 13.8 %. Eight pathogenic mutations were identified in non-BRCA genes associated with DNA damage response pathway. Ten novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. Comparison of allele-frequency with the global databases like TCGA (The Cancer Genome Atlas), gnomAD and Genome Asia 100 K indicated that the novel mutations were unique. CONCLUSIONS: Our study confirms the major proportion of mutations in BRCA1/2 genes in TNBCs in India. Interestingly, a higher proportion of VUS were found in the non-BRCA genes compared to BRCA1/2 emphasizing the need for functional studies of the non-BRCA genes. Large scale studies are warranted to elucidate the landscape of germline mutations relevant to the Indian population and their probable clinical implications.
SATB2 plays a critical role in pancreatic cancer cell proliferation, migration and T cell cytotoxicity.
Jiang G, Zhou X, Chen S … +6 more , Zhong F, Huang G, Wu B, Mou Q, Jiang G, Lin T
Cancer Genet · 2025 Sep · PMID 40543415 · Publisher ↗
OBJECTIVE: We aimed to investigate the role played by special AT-rich sequence binding protein 2 (SATB2) in the immune system of pancreatic cancer (PC). METHODS: Expression of SATB2 was detected in online databases, PC c...
OBJECTIVE: We aimed to investigate the role played by special AT-rich sequence binding protein 2 (SATB2) in the immune system of pancreatic cancer (PC). METHODS: Expression of SATB2 was detected in online databases, PC cell lines, and PC tumor tissues. The correlation between SATB2 expression and immune cell infiltrations was examined. Cytotoxic activity of T lymphocytes to different PC cell lines was examined using CCK8. The constructed SATB2 overexpression and knockdown vectors were transformed into PC cell lines to detect T lymphocyte activity, cancer cell migration and proliferation levels. Finally, RNA-seq assay was performed on the overexpression and knockdown cell lines to screen for differentially expressed genes and performed qRT-PCR assay. RESULTS: Expression level of SATB2 in tumor tissues was significantly higher than that in normal tissues. SATB2 was associated with levels of multiple immune cells infiltration. SATB2 overexpression can inhibit the cytotoxicity of T lymphocytes in PC patients, promote the migration of PC cells, and increase the proportion of S-phase PC cells. There were 1,997 genes differentially expressed in PC cells after SATB2 overexpression and knockout, and these genes were participated in some immune processes, such as B cell chemotaxis and T cell differentiation. CONCLUSION: SATB2 was highly expressed in PC and correlated with various levels of immune cell infiltration. SATB2 also inhibited the cytotoxicity of T cells and promoted PC cell migration. Altogether, SATB2 is recognized as a potential target for improving PC immunotherapy.
Comprehensive molecular profiling in MOTION study.
Kuznetsova OA, Ivanov MV, Lebedeva AA … +8 more , Tryakin AA, Veselovsky EM, Cheporova MS, Moiseenko FV, Gileva MS, Cherentsova AI, Tiatiushkina AN, Fedyanin MY
Cancer Genet · 2025 Sep · PMID 40532431 · Publisher ↗
INTRODUCTION: Comprehensive molecular profiling (CMP) and molecularly matched therapy (MMT) have uncertain roles in advanced solid tumors. This study evaluates CMP's real-world application in Russia. METHODS: A retrospec...
INTRODUCTION: Comprehensive molecular profiling (CMP) and molecularly matched therapy (MMT) have uncertain roles in advanced solid tumors. This study evaluates CMP's real-world application in Russia. METHODS: A retrospective, multicenter study analyzed CMP data from 448 patients with advanced non-hematologic malignancies (2018-2024). Genomic alterations (GA) were classified by ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). RESULTS: ESCAT tiers included I (15.4 %), II (4.9 %), III (31.5 %), IV (19.6 %), and V/X (28.6 %). Therapy data were available for 374 patients. MMT was recommended for 56.9 % but implemented in only 23.2 % (MMT group, n = 87). MMT group showed better objective response rate (61.3 % vs. 37.1 %, p = 0.001), disease control rate (24.0 % vs. 9.2 %, p = 0.003), and progression-free survival ratio (PFS 2/1) ≥ 1.3 (45.0 % vs. 16.2 %, p < 0.01) compared to non-MMT group (n = 287). Median overall survival (OS) was borderline improved (12 vs. 8 months, HR 0.74, p = 0.06). Reasons for non-MMT management were low GA targetability (40 %), drug unavailability (30 %), clinical decline (23 %), and clinician preference (7 %). Patients with ≤3 prior therapies, ECOG performance status 0-1, and molecular tumor board discussion saw significant OS gains with MMT even for ESCAT III-V GA (5 vs. 18 months, HR 0.25, p < 0.01). CONCLUSION: MMT following CMP offers clinical benefit for selected patients, even with ESCAT III-V GA, underscoring its potential in personalized oncology.
Efficacy of pembrolizumab in MSI-high and BRCA-positive castration-resistant prostate cancer.
Higa K, Yamamoto S, Kurokawa K … +4 more , Watanabe K, Bamba H, Kanaoka S, Nakamura K
Cancer Genet · 2025 Sep · PMID 40527113 · Publisher ↗
This report presents a rare case of metastatic castration-resistant prostate cancer (CRPC) in an adult patient characterized by dual molecular alterations: microsatellite instability-high (MSI-H) and a BRCA2 mutation. De...
This report presents a rare case of metastatic castration-resistant prostate cancer (CRPC) in an adult patient characterized by dual molecular alterations: microsatellite instability-high (MSI-H) and a BRCA2 mutation. Despite initial treatment with castration, Abiraterone, and sequential chemotherapy with docetaxel and cabazitaxel, the patient progressed to CRPC. Genetic testing revealed MSI-H and a BRCA2 mutation, prompting pembrolizumab therapy. The treatment led to a dramatic prostate-specific antigen (PSA) reduction . This case underscores the importance of comprehensive genomic profiling for advanced prostate cancer. MSI-H tumors often respond to immune checkpoint inhibitors (ICIs) such as pembrolizumab, while BRCA2 mutations are associated with poly(ADP-ribose) polymerase inhibitors (PARPi) sensitivity. This dual alteration presents therapeutic challenges, as evidenced by pembrolizumab's remarkable efficacy in this patient, highlighting its potential as a treatment option for MSI-H and BRCA-positive CRPC. Moreover, next-generation sequencing (NGS) played a crucial role in identifying actionable biomarkers not detected by earlier BRCA analyses, emphasizing the necessity of thorough genetic testing. Further research is needed to optimize treatment strategies for cases with coexisting MSI-H and BRCA mutations, including exploring the synergistic effects of ICIs and PARP i. This case demonstrates the promise of pembrolizumab and advances the understanding of genetic testing's role in tailoring therapies for complex molecular profiles in prostate cancer.
METTL3-mediated mA modification of pri-miR-93 promotes hepatocellular carcinoma progression via CDKN1A suppression.
Wang Y, Zhang X, Yang F … +2 more , Shang J, Yang Q
Cancer Genet · 2025 Sep · PMID 40517665 · Publisher ↗
N6-methyladenosine (mA) is the most common RNA modification in eukaryotic transcriptomes and plays a key role in various biological processes. However, its function in disease, particularly in microRNA regulation, remain...
N6-methyladenosine (mA) is the most common RNA modification in eukaryotic transcriptomes and plays a key role in various biological processes. However, its function in disease, particularly in microRNA regulation, remains unclear. Hepatocellular carcinoma (HCC) is a major global health challenge, with high morbidity and mortality rates. Investigating the role of mA modification in HCC may provide valuable insights into its molecular mechanisms. This study found that METTL3, an mA methyltransferase, is significantly upregulated in HCC and is associated with poor prognosis. Bioinformatics analysis of the GSE37001 dataset showed that silencing METTL3 in HepG2 cells suppressed cell cycle-related pathways. Among several candidate miRNAs potentially regulated by METTL3 in an mA-dependent manner, miR-93-5p was selected for further study. Experimental results demonstrated that METTL3-mediated mA modification promotes miR-93-5p expression by facilitating pri-miR-93 processing. Functional assays confirmed that miR-93-5p directly targets CDKN1A and downregulates its expression. Moreover, METTL3 overexpression rescued the effects of METTL3 knockdown on pri-miR-93 mA levels and miR-93-5p expression. Rescue experiments further showed that METTL3 promotes HCC cell proliferation and cell cycle progression while inhibiting apoptosis via the miR-93-5p/CDKN1A axis. In summary, METTL3 is highly expressed in HCC and contributes to tumor progression by promoting miR-93-5p expression through mA modification, thereby suppressing CDKN1A. These findings highlight a potential regulatory mechanism in HCC and suggest that targeting the METTL3/miR-93-5p/CDKN1A axis could be a novel therapeutic strategy.
Acute cardiac dysfunction in patients with ovarian cancer treated with Niraparib due to TFAM mutation: A case series and functional analysis.
Liu F, Liu W, Li D … +3 more , Tu C, Peng X, Wen Y
Cancer Genet · 2025 Sep · PMID 40505291 · Publisher ↗
BACKGROUND: Ovarian cancer is a leading cause of gynecological cancer mortality. Despite Niraparib's efficacy in increasing progression-free survival for recurrent ovarian cancer, its potential cardiotoxic effects are un...
BACKGROUND: Ovarian cancer is a leading cause of gynecological cancer mortality. Despite Niraparib's efficacy in increasing progression-free survival for recurrent ovarian cancer, its potential cardiotoxic effects are underexplored. OBJECTIVE: We performed a case series analysis involving two postmenopausal sisters who developed heart failure subsequent to Niraparib therapy for recurrent ovarian cancer. METHODS: Utilizing targeted next-generation sequencing (NGS), we identified a novel missense mutation c.98T>A in Mitochondrial Transcription Factor A (TFAM) gene, which was subsequently confirmed by Sanger sequencing. To investigate the cardiotoxic effects of Niraparib, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSCCMs) carrying the identified mutation. The impact of the mutation on gene expression and protein levels was evaluated through real-time PCR and Western blot analyses. RESULTS: Two postmenopausal sisters treated with Niraparib suffered significant cardiac dysfunction. NGS identified a novel c.98T>A variant in TFAM gene, resulting in a missense mutation. HEK293T cells transfected with mutant plasmids demonstrated normal expression of full-length TFAM mRNA and protein. hiPSCCMs model revealed the variant alone did not induce cardiomyopathy. However, it predisposed to Niraparib-induced cardiomyopathy-like toxicity, mediated by metabolic dysregulation and increased cellular apoptosis CONCLUSION: Our study revealed a novel TFAM variant which might induce potential cardiovascular toxicity of anticancer Niraparib therapies.
The Interplay of N6-Methyladenosine and Ferroptosis in Cancer: A Promising Therapeutic Avenue.
Roshan M K, Pal R, Kumari S … +2 more , Kumar S, Muthuswamy S
Cancer Genet · 2025 Sep · PMID 40482423 · Publisher ↗
Chemoresistance is an obstacle to the efficacy of chemotherapy in cancer. Numerous preclinical and clinical investigations have concentrated on mitigating drug resistance; nevertheless, chemoresistance remains a predomin...
Chemoresistance is an obstacle to the efficacy of chemotherapy in cancer. Numerous preclinical and clinical investigations have concentrated on mitigating drug resistance; nevertheless, chemoresistance remains a predominant challenge. Recent findings strongly suggest that ferroptosis, a form of non-apoptotic cell death characterized by lipid peroxidation, has been associated with resistance to cancer therapies, and the induction of ferroptosis has been shown to reverse drug resistance. The most common epitranscriptomic modification N6-methyladenosine (m6A) regulates cancer progression by enhancing the stability of oncogenes. Recent evidence suggests that dynamic m6A modifying factors play a role in chemosensitization by increasing the ferroptosis susceptibility. This review explores the mechanisms and significance of ferroptosis, including the role of m6A modifications in regulating ferroptosis-related genes. We discuss potential strategies for enhancing m6A-mediated ferroptosis to increase the effectiveness of chemotherapeutic treatments. Understanding the role of m6A modifications in regulating ferroptosis and their impact on the tumor cell response to chemotherapy could lead to identifying novel therapeutic targets, enhancing the effectiveness of chemotherapy and potentially overcoming chemoresistance.
Profiling of HER2, KRAS, and PIK3CA mutations in uterine cervical neuroendocrine carcinoma and implications for oncogenic driver targeting therapy.
Chao WR, Lee MY, Lee YJ … +4 more , Sheu GT, Chiu HH, Shen HP, Han CP
Cancer Genet · 2025 Sep · PMID 40449138 · Publisher ↗
PURPOSE: Dysregulated HER2-mediated RAS/MAPK and PI3K/AKT signaling drive uncontrolled cell growth and tumorigenesis. Following our prior report of frequent HER2 mutations in advanced uterine cervical neuroendocrine carc...
PURPOSE: Dysregulated HER2-mediated RAS/MAPK and PI3K/AKT signaling drive uncontrolled cell growth and tumorigenesis. Following our prior report of frequent HER2 mutations in advanced uterine cervical neuroendocrine carcinoma (NEC), this study expands the genomic landscape by investigating KRAS and PIK3CA as potential therapeutic targets in a cohort of 12 Taiwanese women with cervical NEC. METHODS: We analyzed 12 histologically confirmed cervical NEC tumor samples from Taiwanese patients. Targeted next-generation sequencing (NGS) was performed using a custom Qiagen GeneRead DNAseq Targeted Panels V2, a clinically relevant tumor panel to detect mutations in key oncogenes. DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tissues, followed by variant analysis to identify pathogenic alterations. RESULTS: Beyond HER2 mutations (41.67 %, 5/12), we detected pathogenic alterations in KRAS (16.67 %, 2/12) and PIK3CA (16.67 %, 2/12) within the same cohort. Concurrent mutations were observed in HER2/KRAS (8.3 %, 1/12) and HER2/PIK3CA (8.3 %, 1/12), indicating potential cooperative effects. CONCLUSION: This study identifies HER2, KRAS, and PIK3CA as potentially critical drivers in cervical NEC, with their co-occurrence highlighting the role of RAS/MAPK and PI3K/AKT pathways in pathogenesis. Dual pathway inhibition with multi-target therapies may enhance efficacy and address resistance in this aggressive, treatment-limited disease. Molecular profiling is essential for precision oncology, paving the way for validating these findings in larger cohorts and developing multi-pathway strategies to improve survival and quality of life.
HRD status variation in consecutive tumour biopsies in a pan-cancer cohort: a descriptive single-center study including patients from the Phase 1 Unit, Copenhagen University Hospital, Rigshospitalet.
Britton RD, Alosi D, Robinson L … +7 more , Buhl IK, Spanggaard I, Højgaard M, Kjeldsen MK, Rossing M, Lassen U, Rohrberg KS
Cancer Genet · 2025 Sep · PMID 40435841 · Publisher ↗
BACKGROUND: Limited data on the evolution of homologous recombination deficiency (HRD) status within the course of disease increases the risk of inaccuracies in deciding on Poly(ADP-ribose) polymerase inhibitor therapy a...
BACKGROUND: Limited data on the evolution of homologous recombination deficiency (HRD) status within the course of disease increases the risk of inaccuracies in deciding on Poly(ADP-ribose) polymerase inhibitor therapy and questions the necessity for confirmatory biopsies in clinical trials. This study aims to assess HRD status over time and its role as a dynamic biomarker. METHODS: Genomic tumour profiles obtained from cancer patients in a Phase 1 Unit were retrospectively analysed. Patients with >1 tumour tissue sample and available genomic tumour profiles were included. HRD scores were assessed according to the method described by Telli et al. (2016). RESULTS: A total of 108 patients were included across 24 cancer diagnoses. A potential therapy-altering shift in HRD status was observed in 17 patients: 12 went from negative to positive HRD status whilst 5 went from positive to negative. DISCUSSION: When testing for HRD, sensitivity to normal tissue in tumour samples has proven more consequential than previously expected. Based on our findings, HRD status rarely changes over time, and changes in HRD scores may not reflect a genuine biological shift. Therefore, patients considered for clinical trials based on historic HRD status may not need confirmatory biopsies after intervening treatment, thereby sparing patients from unnecessary procedures.
Corrigendum to "Omics approaches: Role in acute myeloid leukemia biomarker discovery and therapy" [Cancer Genetics, 2025, Volume: 292-293, Pages: 14-26/https://doi.org/10.1016/j.cancergen.2024.12.006].
Shafiei FS, Abroun S, Vahdat S … +1 more , Rafiee M
Cancer Genet · 2025 Jun · PMID 40398009 · Publisher ↗
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Potential factors underlying the progression of RUNX1-mutated MDS to AML.
Stengel A, Hörst K, Kühn C … +4 more , Meggendorfer M, Kern W, Haferlach T, Haferlach C
Cancer Genet · 2025 Jun · PMID 40393312 · Publisher ↗
This study explores the molecular distinctions between myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with RUNX1 mutations (RUNX1mut), aiming to elucidate factors influencing the progression from MDS to...
This study explores the molecular distinctions between myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with RUNX1 mutations (RUNX1mut), aiming to elucidate factors influencing the progression from MDS to AML. Analyzing 1520 patients (773 AML and 747 MDS cases), RUNX1mut were present in 10 % of MDS and 13 % of AML cases. Interestingly, RUNX1mut were associated with higher blast counts in MDS, suggesting a potential role in disease progression. Despite similar overall survival across subgroups, significant differences in variant allele frequency (VAF) were observed, correlating with blast count. Our study highlights a unique genetic signature in both RUNX1mut MDS and AML: Cytogenetic analysis showed a higher frequency of normal karyotypes in RUNX1mut-MDS compared to RUNX1mut-AML. While only trisomy 8 was found in MDS, trisomies 8, 11, and 13 were detected in RUNX1mut-AML. Notably, MECOM rearrangements, KMT2A-PTD, and FLT3-ITD alterations were exclusive to RUNX1mut-AML. RUNX1 mutations were strongly associated with spliceosome gene mutations, especially in RUNX1mut-MDS. Copy neutral loss of heterozygosity (CN-LOH) involving RUNX1 was detected in 22 % of RUNX1mut-AML cases but was absent in RUNX1mut-MDS. These findings highlight the distinct genetic landscape of RUNX1mut-MDS and AML. Understanding these molecular determinants may enhance monitoring and early intervention strategies for MDS patients at risk of progression to AML.
Glioma grade and mortality in relation to sequence variation in the mitochondrial genome.
Peeri NC, Teer JK, Thompson ZJ … +5 more , Nabors LB, Brooks M, Sologon CM, Williams SL, Egan KM
Cancer Genet · 2025 Jun · PMID 40382795 · Full text
PURPOSE: Glioma arises from glial cells and comprises ∼80 % of malignant adult brain tumors. The polymorphic mitochondrial genome plays a key role in maintaining redox homeostasis and generation of reactive oxygen specie...
PURPOSE: Glioma arises from glial cells and comprises ∼80 % of malignant adult brain tumors. The polymorphic mitochondrial genome plays a key role in maintaining redox homeostasis and generation of reactive oxygen species (ROS). ROS have a well-established role in glial tumors. We investigated associations between germline mtDNA variants and haplogroups with glioma grade and glioblastoma (GBM) survival. METHODS: We conducted germline mtDNA sequencing for 388 patients (300 Caucasians, 88 African Americans [AA]) with incident glioma (105 non-GBM, 283 GBM). Across all patients we identified 1431 homoplasmic mtDNA variants, including 692 variants observed only in Caucasians, 474 only in AAs, and 265 in both groups. We estimated Odds Ratios (OR) and 95 % Confidence Intervals (CI) for mtDNA common variants, haplogroups, and gene variant burden in relation to glioma grade and tertiles of survival in GBM patients. Bonferroni and Benjamini-Hochberg correction were applied for multiple comparisons. RESULTS: No mtDNA haplogroup was associated with glioma grade or patient survival in GBM. Common variants m.3010G>A, m.195T>C, and m.16189T>C were linked to lower-grade glioma risk. For GBM survival, m.1719G>A, m.14766T>C, m.16129G>A, and m.204T>C were associated with a poorer prognosis while variant m.73A>G was associated with an improved prognosis. A higher variant burden in MT-ND1 and MT-ND5 was associated with a better prognosis. No results remained statistically significant after correction. CONCLUSION: This is the first comprehensive study of germline mtDNA sequence variation in relation to glioma grade at diagnosis and gliobastoma patient survival. Results warrant further study in larger populations and investigation of biologic mechanisms linking mtDNA polymorphism to these endpoints.
Mechanistic study of Liquiritigenin inhibiting bladder cancer cell proliferation and migration by regulating STING1.
Li W, Yin Q, Qiu Y … +8 more , Liu J, Wang J, Li C, Zhang D, Zhang P, Lv H, Lv Y, Wang Y
Cancer Genet · 2025 Jun · PMID 40347832 · Publisher ↗
BACKGROUND: Bladder cancer (BLCA) is the most common malignant tumor in the urinary system, with a significantly higher incidence in men than in women, severely impacting quality of life. The STING1 gene (stimulator of i...
BACKGROUND: Bladder cancer (BLCA) is the most common malignant tumor in the urinary system, with a significantly higher incidence in men than in women, severely impacting quality of life. The STING1 gene (stimulator of interferon genes 1) plays a critical role in innate immunity by recognizing abnormal DNA and activating immune signaling pathways, promoting the expression of type I interferons and pro-inflammatory cytokines, thereby enhancing anti-tumor immune responses. Liquiritigenin (LQG), a flavonoid compound extracted from licorice, exhibits anti-inflammatory, antioxidant, and anti-cancer properties, capable of inhibiting tumor cell proliferation and invasion while regulating autophagy. This study aims to evaluate the role of LQG in regulating the STING1 gene and its anti-cancer mechanisms in bladder cancer. METHODS: This study employed a multidimensional approach, combining bioinformatics analysis with both in vitro and in vivo experimental validation. Bioinformatics was utilized to assess the expression, function, and immune-related analyses of the STING1 gene. In vitro experiments included CCK-8 assays and colony formation assays to evaluate cell proliferation; Transwell migration assays and wound healing assays to assess migratory capacity; flow cytometry to analyze apoptosis; and immunofluorescence to observe the accumulation of autophagosomes. Additionally, molecular docking analysis was conducted to explore the interaction between LQG and the STING protein, while Western blotting was used to elucidate key molecular pathways. In vivo studies employed a mouse xenograft tumor model to systematically evaluate the anti-tumor effects and safety of LQG. RESULTS: The results showed that STING1 expression was significantly lower in bladder cancer tissues compared to normal tissues. Functional enrichment analysis indicated a close relationship between STING1 and immune response regulation. High STING1 expression was positively associated with different types of immune cells and important immune checkpoints. Analysis of immunotherapy indicated that high STING1 expression was associated with favorable clinical responses. Molecular docking confirmed that LQG directly targets the STING protein. Experimental results demonstrated that LQG inhibits tumor cell survival by targeting STING and blocking autophagic flux. Additionally, LQG downregulated the expression of MMP2 and MMP9, inhibiting migration and invasion, while enhancing apoptosis by modulating Bcl-2, Bax, and caspase-3 levels. CONCLUSION: These findings underscore the critical role of STING1 in the immunobiology of bladder cancer, indicating its potential as a therapeutic target and biomarker for immunotherapy. The novel STING agonist LQG has multiple anti-tumor effects, including the modulation of apoptosis, inhibition of invasion, and enhancement of immune responses. This paves the way for future STING-targeted therapies in bladder cancer treatment.
PLAU serves as a prognostic biomarker correlated with perineural invasion in HNSCC.
Yin H, Zhang Z, Zhang Q … +5 more , You Y, Zhang Z, Han Y, Zhang Q, You B
Cancer Genet · 2025 Jun · PMID 40319793 · Publisher ↗
In head and neck squamous cell carcinoma (HNSCC), perineural invasion (PNI) is a distinctive clinicopathologic feature associated with poor survival. To improve patient prognosis, our investigation delved into the underl...
In head and neck squamous cell carcinoma (HNSCC), perineural invasion (PNI) is a distinctive clinicopathologic feature associated with poor survival. To improve patient prognosis, our investigation delved into the underlying mechanism of PNI in HNSCC, especially laryngeal cancer and hypopharyngeal carcinoma. Based on data from the Cancer Genome Atlas (TCGA), genes were categorized into two groups based on the presence or absence of PNI. Plasminogen activator urokinase (PLAU) was screened out as the key molecular. Next, a tissue microarray comprising 68 patients with HNSCC was used to explore the association between PLAU and nerve growth factor (NGF), a positive control of PNI. Then, the co-culture model and cell damage function experiments were used to investigate the carcinogenic effect of PLAU. CCK8 and Transwell assays confirmed the role of PLAU in promoting proliferation and metastasis. The PC12 neurite growth assay and the co-culture system suggested that PLAU influences malignant behaviors by facilitating PNI. Moreover, introducing small molecule compounds to impede PLAU and NGF can effectively revert tumor progression in vivo. PLAU promotes tumor malignancy by facilitating PNI in HNSCC, offering a novel reference for clarifying the molecular mechanisms underlying PNI and identifying potential therapeutic targets for HNSCC.
Metformin regulates ferroptosis in Skin cutaneous melanoma via ATF3/NRF2 axis.
Gu D, Sun Y, Wang J … +3 more , Sun J, Lou H, Kang W
Cancer Genet · 2025 Jun · PMID 40318300 · Publisher ↗
BACKGROUND: To explore the effects of metformin on the proliferation and ferroptosis of skin cutaneous melanoma (SKCM) and its potential molecular mechanisms, providing a new theoretical basis and strategy for the treatm...
BACKGROUND: To explore the effects of metformin on the proliferation and ferroptosis of skin cutaneous melanoma (SKCM) and its potential molecular mechanisms, providing a new theoretical basis and strategy for the treatment of cutaneous melanoma. METHODS: The CCK-8 experiment was used to detect the effect of metformin on the proliferation of skin cutaneous melanoma cells. Kits were used to detect glutathione (GSH) content, reactive oxygen species (ROS), lipid peroxide (LPO), and malondialdehyde (MDA) levels to evaluate ferroptosis-related indicators. RNA-seq sequencing and related analyses were used to screen differentially expressed genes and explore their involved biological functions and signaling pathways. Western blot was used to detect the expression levels of ATF3 and NRF2 proteins and analyze the regulatory effect of metformin on the ATF3/NRF2 axis. RESULTS: Metformin significantly reduced the proliferation ability of skin cutaneous melanoma cells. The treated cells showed a decrease in GSH content and an accumulation of ROS, LPO, and MDA, suggesting that ferroptosis was regulated. RNA-seq analysis found 2068 differentially expressed genes, of which 897 were up-regulated and 1171 were down-regulated. The related pathways such as iron metabolism disorders and ferroptosis were activated. After metformin treatment, the expression of ATF3 mRNA in cells increased and was positively correlated with the concentration, while the expression in SKCM tissues decreased. At the same time, the expression of ATF3 protein increased and the expression of NRF2 protein decreased, suggesting that metformin may induce ferroptosis through the ATF3/NRF2 axis. CONCLUSION: Metformin can induce ferroptosis by regulating ATF3/NRF2 axis, which may be a novel strategy for improving the treatment of skin cutaneous melanoma.
Rab5if is a potential therapeutic target of NSCLC.
Lu L, Chen L, Gao F … +3 more , Xu C, Ni C, Qian W
Cancer Genet · 2025 Jun · PMID 40318299 · Publisher ↗
PURPOSE: Due to disease progression and drug resistance, non-small cell lung cancer(NSCLC) mortality remains high, and the study of new targets that can inhibit tumor growth is very necessary. The purpose of this study w...
PURPOSE: Due to disease progression and drug resistance, non-small cell lung cancer(NSCLC) mortality remains high, and the study of new targets that can inhibit tumor growth is very necessary. The purpose of this study was to investigate the role of Rab5if in the occurrence and development of NSCLC and explore its potential role in the treatment of NSCLC. MATERIALS AND METHODS: Rab5if overexpression and knockdown non-small cell lung cancer cell lines were constructed by lentivirus. Cellular assays were conducted to assess the impact of Rab5if on the functionality of lung cancer cells, The mechanism by which Rab5if influences the function of lung cancer cells was confirmed through Western blot analysis. The in vivo experiment was used to further verify the results of the in vitro experiment. RESULTS: Bioinformatics research found Rab5if mRNA increased in patients with NSCLC. Increased mRNA and protein levels of Rab5if were confirmed in local human NSCLC tissues. Knockdown of Rab5if in NSCLC cell lines by lentivirus significantly inhibited cell vigour, propagation and migration. In addition, mitochondrial function was impaired in lung cancer cells after Rab5if knockdown. In contrast, Rab5if overexpression promoted the proliferation and migration of NSCLC. Moreover, the impact Rab5if on the function of lung cancer cells was realized through the AKT-mTOR pathway. In the in vivo study, growth inhibition were observed in lung cancer xenografts transfected with Rab5if shRNA in nude mice. Similarly, xenografts of nude mice overexpressing Rab5if grew rapidly. The same pathway as in vitro was confirmed in vivo. CONCLUSION: Rab5if is expected to be a novel therapeutic target for NSCLC.
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