Pub Date : 2025-09-01Epub Date: 2025-06-01DOI: 10.1016/j.cancergen.2025.05.007
Kirthik Roshan M , Rituparna Pal , Subhadra Kumari, Santosh Kumar, Srinivasan Muthuswamy
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.
{"title":"The Interplay of N6-Methyladenosine and Ferroptosis in Cancer: A Promising Therapeutic Avenue","authors":"Kirthik Roshan M , Rituparna Pal , Subhadra Kumari, Santosh Kumar, Srinivasan Muthuswamy","doi":"10.1016/j.cancergen.2025.05.007","DOIUrl":"10.1016/j.cancergen.2025.05.007","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 15-24"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-07-17DOI: 10.1016/j.cancergen.2025.07.010
Atika Dogra , Yasha Hasija
Oral cancer is among the top malignancies and the leading cause of death worldwide. Poor outcomes are attributed to local recurrence and distant metastasis of disease. There is an urgent need to identify the potential biomarkers that may help in prognostication and management of oral cancer. This study aimed to find potential prognostic biomarkers for oral squamous cell carcinoma (OSCC) using eXplainable artificial intelligence (XAI). After the curation of microarray data from GSE31056 (38 relapsed and 58 non-relapsed OSCC samples/ normal oral tissue samples), the application of XAI on Extreme Gradient Boosting algorithm machine learning (ML) models trained on binary classification datasets was employed. After successfully incorporating SHapley Additive exPlanations values into the ML models, 20 top significant genes associated with the relapse of OSCC were identified. The key genes included FAM49B, TTC39A, IFI16, ANGPTL4, HSPH1, GRIA2, SERF2 and others which contribute crucially to cell growth, cell invasion, apoptosis, disease progression, overall survival and disease-free survival. Further, a network of genes and their targeting microRNAs (miRNAs) revealed that miRNAs hsa-let-7b-5p, hsa-miR-27a-3p and hsa-miR-124–3p, had the highest interactions with genes. The predicted genes and miRNAs might be worthy prognostic markers and open the possibilities to understand the underlying pathways and recognize therapeutic targets for aggressive OSCC.
{"title":"Unraveling prognostic biomarkers in oral squamous cell carcinoma: An approach based on explainable artificial intelligence","authors":"Atika Dogra , Yasha Hasija","doi":"10.1016/j.cancergen.2025.07.010","DOIUrl":"10.1016/j.cancergen.2025.07.010","url":null,"abstract":"<div><div>Oral cancer is among the top malignancies and the leading cause of death worldwide. Poor outcomes are attributed to local recurrence and distant metastasis of disease. There is an urgent need to identify the potential biomarkers that may help in prognostication and management of oral cancer. This study aimed to find potential prognostic biomarkers for oral squamous cell carcinoma (OSCC) using eXplainable artificial intelligence (XAI). After the curation of microarray data from GSE31056 (38 relapsed and 58 non-relapsed OSCC samples/ normal oral tissue samples), the application of XAI on Extreme Gradient Boosting algorithm machine learning (ML) models trained on binary classification datasets was employed. After successfully incorporating SHapley Additive exPlanations values into the ML models, 20 top significant genes associated with the relapse of OSCC were identified. The key genes included FAM49B, TTC39A, IFI16, ANGPTL4, HSPH1, GRIA2, SERF2 and others which contribute crucially to cell growth, cell invasion, apoptosis, disease progression, overall survival and disease-free survival. Further, a network of genes and their targeting microRNAs (miRNAs) revealed that miRNAs hsa-let-7b-5p, hsa-miR-27a-3p and hsa-miR-124–3p, had the highest interactions with genes. The predicted genes and miRNAs might be worthy prognostic markers and open the possibilities to understand the underlying pathways and recognize therapeutic targets for aggressive OSCC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 163-171"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144703087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-05-20DOI: 10.1016/j.cancergen.2025.05.004
Rosa Damkjær Britton , Daniela Alosi , Luca Robinson , Ida Kappel Buhl , Iben Spanggaard , Martin Højgaard , Maj Kamille Kjeldsen , Maria Rossing , Ulrik Lassen , Kristoffer Staal Rohrberg
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.
背景：在疾病过程中同源重组缺陷（HRD）状态演变的有限数据增加了决定Poly（adp -核糖）聚合酶抑制剂治疗不准确的风险，并质疑在临床试验中进行确证性活检的必要性。本研究旨在评估HRD随时间的状态及其作为动态生物标志物的作用。方法回顾性分析1期临床癌症患者的基因组肿瘤谱。纳入了1份肿瘤组织样本和可用的肿瘤基因组图谱的患者。HRD评分根据Telli et al.（2016）描述的方法进行评估。结果24例肿瘤诊断共纳入108例患者。在17例患者中观察到HRD状态的潜在治疗改变：12例HRD状态从阴性变为阳性，5例HRD状态从阳性变为阴性。当HRD检测时，对肿瘤样本中正常组织的敏感性已被证明比先前预期的更为重要。根据我们的研究结果，HRD状态很少随时间变化，HRD评分的变化可能不能反映真正的生物学变化。因此，根据历史HRD状态考虑进行临床试验的患者在干预治疗后可能不需要确认性活检，从而使患者免于不必要的手术。
{"title":"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","authors":"Rosa Damkjær Britton , Daniela Alosi , Luca Robinson , Ida Kappel Buhl , Iben Spanggaard , Martin Højgaard , Maj Kamille Kjeldsen , Maria Rossing , Ulrik Lassen , Kristoffer Staal Rohrberg","doi":"10.1016/j.cancergen.2025.05.004","DOIUrl":"10.1016/j.cancergen.2025.05.004","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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).</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Discussion</h3><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 1-8"},"PeriodicalIF":1.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144138605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Immune prognostic model for glioblastoma based on the ssGSEA enrichment score","authors":"Takanari Okamoto , Ryo Mizuta , Ayako Demachi-Okamura , Daisuke Muraoka , Eiichi Sasaki , Katsuhiro Masago , Rui Yamaguchi , Satoshi Teramukai , Yoshihiro Otani , Isao Date , Shota Tanaka , Yoshinobu Takahashi , Naoya Hashimoto , Hirokazu Matsushita","doi":"10.1016/j.cancergen.2025.03.005","DOIUrl":"10.1016/j.cancergen.2025.03.005","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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 (<em>p</em> < 0.001 and <em>p</em> = 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 (<em>p</em> < 0.01) across all cohorts.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 32-41"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143681123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-03-27DOI: 10.1016/j.cancergen.2025.03.007
Dongling He , Qing Lv , Bin Li , Min Xu , Dewen Jiang , Zhi Tang , Yanjie Liu
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.
{"title":"Study on the correlation between BRCA1 gene polymorphism and hrHPV infection in cervical precancerous lesions","authors":"Dongling He , Qing Lv , Bin Li , Min Xu , Dewen Jiang , Zhi Tang , Yanjie Liu","doi":"10.1016/j.cancergen.2025.03.007","DOIUrl":"10.1016/j.cancergen.2025.03.007","url":null,"abstract":"<div><div>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 (<em>p</em> < 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 (<em>p</em> < 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).</div><div>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 (<em>P</em> < 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 (<em>P</em> < 0.05). The percentage of cells in the S phase decreased in the downregulated group compared to the control group (<em>P</em> < 0.05), and the proportion of cells in the G2 phase increased in the overexpression group compared to the control group (<em>P</em> < 0.05), BRCA1 may be involved in the migration and cell cycle of HeLa cells.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 99-110"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143839099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-04-24DOI: 10.1016/j.cancergen.2025.04.005
Linjuan Lu , Lixiu Chen , Feng Gao , Chunming Xu , Chen Ni , Wenxia Qian
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.
{"title":"Rab5if is a potential therapeutic target of NSCLC","authors":"Linjuan Lu , Lixiu Chen , Feng Gao , Chunming Xu , Chen Ni , Wenxia Qian","doi":"10.1016/j.cancergen.2025.04.005","DOIUrl":"10.1016/j.cancergen.2025.04.005","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Materials and Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>Rab5if is expected to be a novel therapeutic target for NSCLC.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 123-135"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143895797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-04-12DOI: 10.1016/j.cancergen.2025.04.003
Panagiota Fallon , Anna Boulouta , Constantina Papacharalambous , Anastasios Kyriazoglou , Panagiotis J. Vlachostergios
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.
{"title":"Ewing sarcoma of the rib with a rare PTEN mutation","authors":"Panagiota Fallon , Anna Boulouta , Constantina Papacharalambous , Anastasios Kyriazoglou , Panagiotis J. Vlachostergios","doi":"10.1016/j.cancergen.2025.04.003","DOIUrl":"10.1016/j.cancergen.2025.04.003","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Case Presentation</h3><div>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 <em>PTEN</em> c.640C><em>T</em>(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.</div></div><div><h3>Conclusions</h3><div><em>PTEN</em> 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 <em>PTEN</em> inactivation, could help improve outcomes in selected cases.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 90-93"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Clinicopathological correlation of PTPN3 expression in breast cancer and in silico drug screening against PTPN3 for therapeutics","authors":"Sanu Thankachan , Boddapati Kalyani Bhardwaj , Dimple Patel , Kavitha KP , Shama Prasada Kabekkodu , Padmanaban S Suresh","doi":"10.1016/j.cancergen.2025.04.004","DOIUrl":"10.1016/j.cancergen.2025.04.004","url":null,"abstract":"<div><div>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 (<em>p</em> < 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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 111-122"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"HSP110 T17 marker matches the pentaplex panel and outperforms CAT-25 for detecting microsatellite instability in sporadic colorectal cancer","authors":"Nasreddine Rajoua , Antoine Daunay , Wissem Triki , Oussema Baraket , Sami Bouchoucha , Houcine Maghrebi , Aymen Mabrouk , Jean-François Deleuze , Alexandre How-Kit , Maher Kharrat","doi":"10.1016/j.cancergen.2025.03.002","DOIUrl":"10.1016/j.cancergen.2025.03.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 21-26"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01Epub Date: 2025-04-27DOI: 10.1016/j.cancergen.2025.04.008
Haimeng Yin , Zixiang Zhang , Qing Zhang , Yiwen You , Zhenxin Zhang , Yumo Han , Qicheng Zhang , Bo You
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.
{"title":"PLAU serves as a prognostic biomarker correlated with perineural invasion in HNSCC","authors":"Haimeng Yin , Zixiang Zhang , Qing Zhang , Yiwen You , Zhenxin Zhang , Yumo Han , Qicheng Zhang , Bo You","doi":"10.1016/j.cancergen.2025.04.008","DOIUrl":"10.1016/j.cancergen.2025.04.008","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 145-155"},"PeriodicalIF":1.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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