Pub Date : 2025-05-25DOI: 10.1016/j.cancergen.2025.05.006
Fei Liu , Wen Liu , Danya Li , Chunhua Tu , Xiaoping Peng , Yuan Wen
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.
{"title":"Acute cardiac dysfunction in patients with ovarian cancer treated with Niraparib due to TFAM mutation: A case series and functional analysis","authors":"Fei Liu , Wen Liu , Danya Li , Chunhua Tu , Xiaoping Peng , Yuan Wen","doi":"10.1016/j.cancergen.2025.05.006","DOIUrl":"10.1016/j.cancergen.2025.05.006","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Objective</h3><div>We performed a case series analysis involving two postmenopausal sisters who developed heart failure subsequent to Niraparib therapy for recurrent ovarian cancer.</div></div><div><h3>Methods</h3><div>Utilizing targeted next-generation sequencing (NGS), we identified a novel missense mutation c.98T>A in Mitochondrial Transcription Factor A (<em>TFAM</em>) gene, which was subsequently confirmed by Sanger sequencing. To investigate the cardiotoxic effects of Niraparib, we generated human induced pluripotent stem cell-derived cardiomyocytes (hiPSC<img>CMs) 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.</div></div><div><h3>Results</h3><div>Two postmenopausal sisters treated with Niraparib suffered significant cardiac dysfunction. NGS identified a novel c.98T>A variant in <em>TFAM</em> gene, resulting in a missense mutation. HEK293T cells transfected with mutant plasmids demonstrated normal expression of full-length <em>TFAM</em> mRNA and protein. hiPSC<img>CMs 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</div></div><div><h3>Conclusion</h3><div>Our study revealed a novel <em>TFAM</em> variant which might induce potential cardiovascular toxicity of anticancer Niraparib therapies.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 25-30"},"PeriodicalIF":1.4,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263273","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 : 2025-05-24DOI: 10.1016/j.cancergen.2025.05.005
Wan-Ru Chao , Ming-Yung Lee , Yi-Ju Lee , Gwo-Tarng Sheu , Hsiu-Hsiu Chiu , Huang-Pin Shen , Chih-Ping Han
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.
{"title":"Profiling of HER2, KRAS, and PIK3CA mutations in uterine cervical neuroendocrine carcinoma and implications for oncogenic driver targeting therapy","authors":"Wan-Ru Chao , Ming-Yung Lee , Yi-Ju Lee , Gwo-Tarng Sheu , Hsiu-Hsiu Chiu , Huang-Pin Shen , Chih-Ping Han","doi":"10.1016/j.cancergen.2025.05.005","DOIUrl":"10.1016/j.cancergen.2025.05.005","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>Beyond <em>HER2</em> mutations (41.67 %, 5/12), we detected pathogenic alterations in <em>KRAS</em> (16.67 %, 2/12) and <em>PIK3CA</em> (16.67 %, 2/12) within the same cohort. Concurrent mutations were observed in <em>HER2</em>/<em>KRA</em>S (8.3 %, 1/12) and <em>HER2</em>/<em>PIK3CA</em> (8.3 %, 1/12), indicating potential cooperative effects.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"296 ","pages":"Pages 9-14"},"PeriodicalIF":1.4,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177700","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 : 2025-05-20DOI: 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":"2025-05-20","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}
Pub Date : 2025-05-15DOI: 10.1016/j.cancergen.2025.05.003
Anna Stengel, Katharina Hörst, Constanze Kühn, Manja Meggendorfer, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach
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.
{"title":"Potential factors underlying the progression of RUNX1-mutated MDS to AML","authors":"Anna Stengel, Katharina Hörst, Constanze Kühn, Manja Meggendorfer, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach","doi":"10.1016/j.cancergen.2025.05.003","DOIUrl":"10.1016/j.cancergen.2025.05.003","url":null,"abstract":"<div><div>This study explores the molecular distinctions between myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with <em>RUNX1</em> mutations (<em>RUNX1</em>mut), aiming to elucidate factors influencing the progression from MDS to AML. Analyzing 1520 patients (773 AML and 747 MDS cases), <em>RUNX1</em>mut were present in 10 % of MDS and 13 % of AML cases. Interestingly, <em>RUNX1</em>mut 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 <em>RUNX1</em>mut MDS and AML: Cytogenetic analysis showed a higher frequency of normal karyotypes in <em>RUNX1</em>mut-MDS compared to <em>RUNX1</em>mut-AML. While only trisomy 8 was found in MDS, trisomies 8, 11, and 13 were detected in <em>RUNX1</em>mut-AML. Notably, <em>MECOM</em> rearrangements, <em>KMT2A</em>-PTD, and <em>FLT3</em>-ITD alterations were exclusive to RUNX1mut-AML. <em>RUNX1</em> mutations were strongly associated with spliceosome gene mutations, especially in <em>RUNX1</em>mut-MDS. Copy neutral loss of heterozygosity (CN-LOH) involving <em>RUNX1</em> was detected in 22 % of <em>RUNX1</em>mut-AML cases but was absent in <em>RUNX1</em>mut-MDS. These findings highlight the distinct genetic landscape of <em>RUNX1</em>mut-MDS and AML. Understanding these molecular determinants may enhance monitoring and early intervention strategies for MDS patients at risk of progression to AML.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 181-183"},"PeriodicalIF":1.4,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144090362","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 : 2025-05-12DOI: 10.1016/j.cancergen.2025.05.001
Noah C. Peeri , Jamie K. Teer , Zachary J. Thompson , L. Burt Nabors , Marisa Brooks , Corneliu M. Sologon , Sion L. Williams , Kathleen M. Egan
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.
{"title":"Glioma grade and mortality in relation to sequence variation in the mitochondrial genome","authors":"Noah C. Peeri , Jamie K. Teer , Zachary J. Thompson , L. Burt Nabors , Marisa Brooks , Corneliu M. Sologon , Sion L. Williams , Kathleen M. Egan","doi":"10.1016/j.cancergen.2025.05.001","DOIUrl":"10.1016/j.cancergen.2025.05.001","url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>No mtDNA haplogroup was associated with glioma grade or patient survival in GBM. Common variants m.3010G><em>A</em>, m.195T><em>C</em>, and m.16189T><em>C</em> were linked to lower-grade glioma risk. For GBM survival, m.1719G><em>A</em>, m.14766T><em>C</em>, m.16129G><em>A</em>, and m.204T><em>C</em> were associated with a poorer prognosis while variant m.73A><em>G</em> was associated with an improved prognosis. A higher variant burden in <em>MT-ND1</em> and <em>MT-ND5</em> was associated with a better prognosis. No results remained statistically significant after correction.</div></div><div><h3>Conclusion</h3><div>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.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 171-180"},"PeriodicalIF":1.4,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144071311","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 : 2025-04-27DOI: 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":"2025-04-27","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}
Pub Date : 2025-04-27DOI: 10.1016/j.cancergen.2025.04.007
Wuheng Li , Qiang Yin , Yihang Qiu , Jiasheng Liu , Jiaxin Wang , Chengxi Li , Dongchao Zhang , Peng Zhang , Haolong Lv , Yue Lv , Yongquan Wang
<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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
{"title":"Mechanistic study of Liquiritigenin inhibiting bladder cancer cell proliferation and migration by regulating STING1","authors":"Wuheng Li , Qiang Yin , Yihang Qiu , Jiasheng Liu , Jiaxin Wang , Chengxi Li , Dongchao Zhang , Peng Zhang , Haolong Lv , Yue Lv , Yongquan Wang","doi":"10.1016/j.cancergen.2025.04.007","DOIUrl":"10.1016/j.cancergen.2025.04.007","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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 ","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 156-170"},"PeriodicalIF":1.4,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143924603","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 : 2025-04-26DOI: 10.1016/j.cancergen.2025.04.006
Da Gu , Yulin Sun , Jianghui Wang , Jinpeng Sun , Huanmin Lou , Weiting Kang
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.
{"title":"Metformin regulates ferroptosis in Skin cutaneous melanoma via ATF3/NRF2 axis","authors":"Da Gu , Yulin Sun , Jianghui Wang , Jinpeng Sun , Huanmin Lou , Weiting Kang","doi":"10.1016/j.cancergen.2025.04.006","DOIUrl":"10.1016/j.cancergen.2025.04.006","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>Metformin can induce ferroptosis by regulating ATF3/NRF2 axis, which may be a novel strategy for improving the treatment of skin cutaneous melanoma.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"294 ","pages":"Pages 136-144"},"PeriodicalIF":1.4,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899265","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 : 2025-04-24DOI: 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":"2025-04-24","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}
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