Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102239
Dong Luo , Yixiong Li , Xiao Yu , Liandong Ji , Xuejun Gong
Early-onset pancreatic cancer (EOPC) is usually defined as patients with pancreatic cancer before the age of 50 years, which is relatively rare. However, the research on EOPC is somewhat obscure, and the specific clinical and molecular characteristics of this condition are debated. In this review, we discussed the differences between EOPC and late-onset pancreatic cancer (LOPC) or average-onset pancreatic cancer (AOPC) with a focus on clinical and molecular characteristics, survival outcomes and treatment to promote the diagnosis and treatment of EOPC.
{"title":"Early onset pancreatic cancer: A review","authors":"Dong Luo , Yixiong Li , Xiao Yu , Liandong Ji , Xuejun Gong","doi":"10.1016/j.tranon.2024.102239","DOIUrl":"10.1016/j.tranon.2024.102239","url":null,"abstract":"<div><div>Early-onset pancreatic cancer (EOPC) is usually defined as patients with pancreatic cancer before the age of 50 years, which is relatively rare. However, the research on EOPC is somewhat obscure, and the specific clinical and molecular characteristics of this condition are debated. In this review, we discussed the differences between EOPC and late-onset pancreatic cancer (LOPC) or average-onset pancreatic cancer (AOPC) with a focus on clinical and molecular characteristics, survival outcomes and treatment to promote the diagnosis and treatment of EOPC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102239"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102228
Martina Ruglioni , Iacopo Petrini , Stefania Crucitta , Andrea Sbrana , Giovanna Irene Luculli , Leila Sadeghi Gol , Carola Forte , Antonio Chella , Christian Rolfo , Romano Danesi , Marzia Del Re
Background
Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.
Methods
Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.
Results
A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA (“shedders”). Higher ECOG PS (p = 0.04), bilateral localization of primary tumor (p = 0.04), and the presence of intrathoracic/extrathoracic disease (p = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (p = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (p = 0.05).
Conclusion
Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.
{"title":"Clinical characteristics of EGFR-ctDNA shedders in EGFR-mutant NSCLC patients","authors":"Martina Ruglioni , Iacopo Petrini , Stefania Crucitta , Andrea Sbrana , Giovanna Irene Luculli , Leila Sadeghi Gol , Carola Forte , Antonio Chella , Christian Rolfo , Romano Danesi , Marzia Del Re","doi":"10.1016/j.tranon.2024.102228","DOIUrl":"10.1016/j.tranon.2024.102228","url":null,"abstract":"<div><h3>Background</h3><div>Circulating tumor DNA (ctDNA) revolutionized the molecular diagnostics of lung cancer by enabling non-invasive, sensitive identification of actionable mutations. However, ctDNA analysis may be challenging due to tumor shedding variability, leading to false negative results. This study aims to understand the determinants for ctDNA shedding based on clinical characteristics of lung cancer patients, for a better interpretation of false negative results to be considered when ordering ctDNA analysis for clinical practice.</div></div><div><h3>Methods</h3><div>Blood samples were collected from patients with stage IV EGFR-mutated (mEGFR) NSCLC before treatment and monitored until disease progression. EGFR was assessed on tissue by standard procedures, while EGFR status on ctDNA was tested using dPCR at baseline and at the first reassessment. NGS was used to evaluate patients mutational status at the progression of the disease.</div></div><div><h3>Results</h3><div>A total of 40 mEGFR tissue samples were collected. Plasma samples were analyzed for mEGFR before starting the first line, 65 % of patients had detectable mEGFR in ctDNA (“shedders”). Higher ECOG PS (<em>p</em> = 0.04), bilateral localization of primary tumor (<em>p</em> = 0.04), and the presence of intrathoracic/extrathoracic disease (<em>p</em> = 0.05), were associated to mEGFR shedding. Shedders had shorter PFS compared to non-shedders (<em>p</em> = 0.03). Patients with detectable mEGFR in ctDNA at the first radiological assessment exhibited worse PFS compared to patients with ctDNA clearance (<em>p</em> = 0.05).</div></div><div><h3>Conclusion</h3><div>Our preliminary data demonstrate that specific clinical characteristics predict mEGFR shedding in ctDNA of NSCLC, suggesting a potential clinical applicability for understanding potential false negative results and appropriate reporting in clinical practice.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102228"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102266
Romy Walker , Jihoon E. Joo , Khalid Mahmood , Mark Clendenning , Julia Como , Susan G. Preston , Sharelle Joseland , Bernard J. Pope , Ana B.D. Medeiros , Brenely V. Murillo , Nicholas Pachter , Kevin Sweet , Allan D. Spigelman , Alexandra Groves , Margaret Gleeson , Krzysztof Bernatowicz , Nicola Poplawski , Lesley Andrews , Emma Healey , Steven Gallinger , Peter Georgeson
Background
Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.
Methods
Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.
Results
In biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, p-value=3.4 × 10–4). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, p-value=5.1 × 10–7). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.
Conclusions
SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.
{"title":"Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications","authors":"Romy Walker , Jihoon E. Joo , Khalid Mahmood , Mark Clendenning , Julia Como , Susan G. Preston , Sharelle Joseland , Bernard J. Pope , Ana B.D. Medeiros , Brenely V. Murillo , Nicholas Pachter , Kevin Sweet , Allan D. Spigelman , Alexandra Groves , Margaret Gleeson , Krzysztof Bernatowicz , Nicola Poplawski , Lesley Andrews , Emma Healey , Steven Gallinger , Peter Georgeson","doi":"10.1016/j.tranon.2024.102266","DOIUrl":"10.1016/j.tranon.2024.102266","url":null,"abstract":"<div><h3>Background</h3><div>Colorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in <em>MUTYH</em> or <em>NTHL1</em> exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic <em>MUTYH</em> cases, on 7 adenomas and 2 CRCs from 5 biallelic <em>NTHL1</em> cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures.</div></div><div><h3>Results</h3><div>In biallelic <em>MUTYH</em> cases, SBS18+SBS36 signature proportions in adenomas (mean±standard deviation, 65.6 %±29.6 %) were not significantly different to those observed in CRCs (76.2 % ± 20.5 %, <em>p-value</em>=0.37), but were significantly higher compared with non-hereditary adenomas (7.6 % ± 7.0 %, <em>p-value</em>=3.4 × 10<sup>–4</sup>). Similarly, in biallelic <em>NTHL1</em> cases, SBS30 signature proportions in adenomas (74.5 %±9.4 %) were similar to those in CRCs (78.8 % ± 2.4 %) but significantly higher compared with non-hereditary adenomas (2.8 % ± 3.6 %, <em>p-value</em>=5.1 × 10<sup>–7</sup>). Additionally, a compound heterozygote with the c.1187G><em>A</em> p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in <em>MUTYH</em> demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic.</div></div><div><h3>Conclusions</h3><div>SBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions to those observed in CRCs from biallelic <em>MUTYH</em> and biallelic <em>NTHL1</em> cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102266"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11774829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2025.102277
Jieming Lu , Zhimin Shen , Xiaoqing Wang , Yanhong Lin , Ziyang Han , Mingqiang Kang
This retrospective cohort study using SEER data from 2000 to 2020 examines the impact of radiotherapy on the risk of Secondary Primary Lung Cancer (SPLC) in 224,396 elderly female breast cancer survivors. Patients treated with radiotherapy displayed a 31 % increased SPLC risk compared to those not treated. Utilizing Cox Proportional Hazards and Poisson regression models, the study assessed various factors including age, race, and tumor characteristics. Propensity Score Matching (PSM) was employed to balance cohorts for survival analysis, which revealed that radiotherapy did not negatively impact overall survival despite the increased risk of SPLC. A nomogram was developed to aid clinical decision-making by predicting survival outcomes. The findings advocate for personalized treatment strategies and continuous monitoring to manage potential long-term adverse effects effectively, highlighting the need for a balanced approach in the treatment of breast cancer survivors.
{"title":"Impact of radiotherapy on secondary lung cancer risk and survival in elderly female breast cancer survivors","authors":"Jieming Lu , Zhimin Shen , Xiaoqing Wang , Yanhong Lin , Ziyang Han , Mingqiang Kang","doi":"10.1016/j.tranon.2025.102277","DOIUrl":"10.1016/j.tranon.2025.102277","url":null,"abstract":"<div><div>This retrospective cohort study using SEER data from 2000 to 2020 examines the impact of radiotherapy on the risk of Secondary Primary Lung Cancer (SPLC) in 224,396 elderly female breast cancer survivors. Patients treated with radiotherapy displayed a 31 % increased SPLC risk compared to those not treated. Utilizing Cox Proportional Hazards and Poisson regression models, the study assessed various factors including age, race, and tumor characteristics. Propensity Score Matching (PSM) was employed to balance cohorts for survival analysis, which revealed that radiotherapy did not negatively impact overall survival despite the increased risk of SPLC. A nomogram was developed to aid clinical decision-making by predicting survival outcomes. The findings advocate for personalized treatment strategies and continuous monitoring to manage potential long-term adverse effects effectively, highlighting the need for a balanced approach in the treatment of breast cancer survivors.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102277"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2025.102272
Ka Zhang , Yi-Wen Zhu , Ao-Qi Tang , Ze-Tao Zhou , Yi-Lun Yang , Zi-Hui Liu , Yan Li , Xiao-Yi Liang , Zhi-Fen Feng , Jun Wang , Tong Jiang , Qi-Ying Jiang , Dong-Dong Wu
The occurrence and development of tumor is mediated by a wide range of complex mechanisms. Subsequent to nitric oxide and carbon monoxide, hydrogen sulfide (H2S) holds the distinction of being the third identified gasotransmitter. Alternation of H2S level has been widely demonstrated to induce an array of disturbances in important cancer cell signaling pathways. As a result, the effects of H2S-catalyzing enzymes in cancers also attract widspread attention. 3-mercaptopyruvate sulfurtransferase (3-MST) is privileged to be one of them. In fact, 3-MST is overexpressed in many tumors including human colon cancer, lung adenocarcinoma, and bladder urothelial carcinoma. But it is also lowly expressed in hepatocellular carcinoma. In this review, we focus on the generation of endogenous H2S and polysulfides, facilitated by 3-MST. Additionally, we delve deeply into the potential role of 3-MST in tumorigenesis and development. The impact of 3-MST inhibition on the development of tumors and its potential for tumor therapy are also highlighted.
{"title":"Role of 3-mercaptopyruvate sulfurtransferase in cancer: Molecular mechanisms and therapeutic perspectives","authors":"Ka Zhang , Yi-Wen Zhu , Ao-Qi Tang , Ze-Tao Zhou , Yi-Lun Yang , Zi-Hui Liu , Yan Li , Xiao-Yi Liang , Zhi-Fen Feng , Jun Wang , Tong Jiang , Qi-Ying Jiang , Dong-Dong Wu","doi":"10.1016/j.tranon.2025.102272","DOIUrl":"10.1016/j.tranon.2025.102272","url":null,"abstract":"<div><div>The occurrence and development of tumor is mediated by a wide range of complex mechanisms. Subsequent to nitric oxide and carbon monoxide, hydrogen sulfide (H<sub>2</sub>S) holds the distinction of being the third identified gasotransmitter. Alternation of H<sub>2</sub>S level has been widely demonstrated to induce an array of disturbances in important cancer cell signaling pathways. As a result, the effects of H<sub>2</sub>S-catalyzing enzymes in cancers also attract widspread attention. 3-mercaptopyruvate sulfurtransferase (3-MST) is privileged to be one of them. In fact, 3-MST is overexpressed in many tumors including human colon cancer, lung adenocarcinoma, and bladder urothelial carcinoma. But it is also lowly expressed in hepatocellular carcinoma. In this review, we focus on the generation of endogenous H<sub>2</sub>S and polysulfides, facilitated by 3-MST. Additionally, we delve deeply into the potential role of 3-MST in tumorigenesis and development. The impact of 3-MST inhibition on the development of tumors and its potential for tumor therapy are also highlighted.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102272"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102231
Carlos M Roggero , Anwesha B Ghosh , Anvita Devineni , Shihong Ma , Eliot Blatt , Ganesh V. Raj , Yi Yin
Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts in vivo and patient-derived explant models ex vivo. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.
{"title":"CDK4/6 inhibitors promote PARP1 degradation and synergize with PARP inhibitors in non-small cell lung cancer","authors":"Carlos M Roggero , Anwesha B Ghosh , Anvita Devineni , Shihong Ma , Eliot Blatt , Ganesh V. Raj , Yi Yin","doi":"10.1016/j.tranon.2024.102231","DOIUrl":"10.1016/j.tranon.2024.102231","url":null,"abstract":"<div><div>Despite widespread deregulation of CDK4/6 activity in non-small cell lung cancer (NSCLC), clinical trials with CDK4/6 inhibitor (CDK4/6i) as a monotherapy have shown poor antitumor activity. Preclinical studies indicate that CDK4/6i may collaborate by influencing DNA damage repair pathways during radiotherapy. Since PARP1 expression was also significantly upregulated in NSCLC, we analyzed the efficacy of combining PARP1 and CDK4/6 inhibition in NSCLC models. We found that CDK4/6is synergize with PARP1 inhibitors (PARPis) to inhibit the clonogenic growth of RB-proficient NSCLC models. This synergy correlates with increased accumulation of DNA damage, interrupted cell-cycle checkpoints, and enhanced apoptotic cell death. Mechanistically, we showed that CDK4/6is promote PARP1 protein degradation, which lead to decreased availability of DNA repair factors involved in homologous recombination and suppression of DNA repair competency. Furthermore, we showed that PARP trapping is engaged in this synergy. We then confirmed that combining PARPi and CDK4/6i blocked the growth of NSCLC xenografts <em>in vivo</em> and patient-derived explant models <em>ex vivo</em>. Our data reveal a previously uncharacterized impact of CDK4/6i on PARP1 levels in RB-proficient NSCLC models and the engagement of PARP trapping in the synergy between CDK4/6i and PARPi. Our findings suggest combining CDK4/6i with PARPi could be a viable therapeutic strategy for patients with RB-proficient NSCLC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102231"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102237
Qing Nian , Yan Lin , Jinhao Zeng , Yanna Zhang , Rongxing Liu
Wilms tumor 1 (WT1) is a multifaceted protein with dual functions, acting both as a tumor suppressor and as a transcriptional activator of oncogenes. WT1 is highly expressed in various types of solid tumors and leukemia, and its elevated expression is associated with a poor prognosis for patients. High WT1 expression also indicates a greater risk of refractory disease or relapse. Consequently, targeting WT1 is an effective strategy for disease prevention and relapse mitigation. Substantial information is available on the pathogenesis of WT1 in various diseases, and several WT1-targeted therapies, including chemical drugs, natural products, and targeted vaccines, are available. We provide a comprehensive review of the mechanisms by which WT1 influences malignancies and summarize the resulting therapeutic approaches thoroughly. This article provides information on the roles of WT1 in the pathogenesis of different cancers and provides insights into drugs and immunotherapies targeting WT1. The goal of this work is to provide a systematic understanding of the current research landscape and of future directions for WT1-related studies.
{"title":"Multifaceted functions of the Wilms tumor 1 protein: From its expression in various malignancies to targeted therapy","authors":"Qing Nian , Yan Lin , Jinhao Zeng , Yanna Zhang , Rongxing Liu","doi":"10.1016/j.tranon.2024.102237","DOIUrl":"10.1016/j.tranon.2024.102237","url":null,"abstract":"<div><div>Wilms tumor 1 (WT1) is a multifaceted protein with dual functions, acting both as a tumor suppressor and as a transcriptional activator of oncogenes. WT1 is highly expressed in various types of solid tumors and leukemia, and its elevated expression is associated with a poor prognosis for patients. High WT1 expression also indicates a greater risk of refractory disease or relapse. Consequently, targeting WT1 is an effective strategy for disease prevention and relapse mitigation. Substantial information is available on the pathogenesis of WT1 in various diseases, and several WT1-targeted therapies, including chemical drugs, natural products, and targeted vaccines, are available. We provide a comprehensive review of the mechanisms by which WT1 influences malignancies and summarize the resulting therapeutic approaches thoroughly. This article provides information on the roles of WT1 in the pathogenesis of different cancers and provides insights into drugs and immunotherapies targeting WT1. The goal of this work is to provide a systematic understanding of the current research landscape and of future directions for WT1-related studies.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102237"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11700300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102242
Zhihui Xi , Huolun Feng , Kunling Chen , Xin Guo , Dandan Zhu , Jiabin Zheng , Yong Li
Importance
Gastric cancer is often diagnosed at an advanced stage and at order age, identification of high-risk population is needed for detection of early-stage gastric cancer.
Objective
To examine whether clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor of gastric cancer.
Design
This cohort study used data from the UK Biobank collected from baseline (2006–2010) to the end of follow-up in March 2024.
Setting
Data on age, sex, race, alcohol consumption, smoking status and type 2 diabetes were collected at baseline interview. Previous and diagnosed cancer or diseases were collected from self-reported and in-hospital records.
Participants
Participants with no previous cancer or hematologic disorders were selected. Participants with gastric cancer cases were aged 60.7 (S.D. 6.62), 71.8 % male; controls were aged 56.1 (S.D. 8.11), 47.4 % male.
Exposures
Whole-exome sequencing was performed on blood samples collected at baseline. A CHIP status was identified based on the mutations on 43 CHIP-related genes.
Main outcomes and measures
Odds ratio (OR) of CHIP with gastric cancer risk was estimated using multivariable logistic regression models. Participants were grouped based on age and CHIP status to examine if there are differences in the cumulative incidence of gastric cancer.
Results
Among 402,253 participants, 1,070 incident gastric cancer cases were identified (mean age, 60.7 ± 6.62 years). The prevalence of CHIP at baseline was associated with an increased risk of gastric cancer (cases: 6.54 % vs. controls 5.14 %; OR without adjustment, 1.29; 95 % CI, 1.004 to 1.63). The stratified OR (95 % CI) of individuals aged ≥ 57 was 1.33 (1.02 to 1.72) for overall CHIP, whereas the OR for younger individuals was 0.79 (0.37 to 1.44). CHIP involving DNMT3A (OR, 1.81; 95 % CI, 1.05 to 2.88; P = 0.0193) and ASXL1 (OR, 2.43; 95 % CI, 0.95 to 4.99; P = 0.032) was associated with an increased risk of gastric cancer. These positive associations remained significantly in sensitivity analyses adjusted by known risk factors. Compared to younger individuals and non-CHIP carriers, older participants with CHIP exhibited a significantly higher cumulative incidence of gastric cancer (P < 0.0001).
Conclusions and relevance
CHIP is associated with gastric cancer in the elderly and contributes to the positive association between DNM3A and ASXL1 mutations and risk of gastric cancer.
{"title":"Clonal hematopoiesis of indeterminate potential is a risk factor of gastric cancer: A Prospective Cohort in UK Biobank study","authors":"Zhihui Xi , Huolun Feng , Kunling Chen , Xin Guo , Dandan Zhu , Jiabin Zheng , Yong Li","doi":"10.1016/j.tranon.2024.102242","DOIUrl":"10.1016/j.tranon.2024.102242","url":null,"abstract":"<div><h3>Importance</h3><div>Gastric cancer is often diagnosed at an advanced stage and at order age, identification of high-risk population is needed for detection of early-stage gastric cancer.</div></div><div><h3>Objective</h3><div>To examine whether clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor of gastric cancer.</div></div><div><h3>Design</h3><div>This cohort study used data from the UK Biobank collected from baseline (2006–2010) to the end of follow-up in March 2024.</div></div><div><h3>Setting</h3><div>Data on age, sex, race, alcohol consumption, smoking status and type 2 diabetes were collected at baseline interview. Previous and diagnosed cancer or diseases were collected from self-reported and in-hospital records.</div></div><div><h3>Participants</h3><div>Participants with no previous cancer or hematologic disorders were selected. Participants with gastric cancer cases were aged 60.7 (S.D. 6.62), 71.8 % male; controls were aged 56.1 (S.D. 8.11), 47.4 % male.</div></div><div><h3>Exposures</h3><div>Whole-exome sequencing was performed on blood samples collected at baseline. A CHIP status was identified based on the mutations on 43 CHIP-related genes.</div></div><div><h3>Main outcomes and measures</h3><div>Odds ratio (OR) of CHIP with gastric cancer risk was estimated using multivariable logistic regression models. Participants were grouped based on age and CHIP status to examine if there are differences in the cumulative incidence of gastric cancer.</div></div><div><h3>Results</h3><div>Among 402,253 participants, 1,070 incident gastric cancer cases were identified (mean age, 60.7 ± 6.62 years). The prevalence of CHIP at baseline was associated with an increased risk of gastric cancer (cases: 6.54 % vs. controls 5.14 %; OR without adjustment, 1.29; 95 % CI, 1.004 to 1.63). The stratified OR (95 % CI) of individuals aged ≥ 57 was 1.33 (1.02 to 1.72) for overall CHIP, whereas the OR for younger individuals was 0.79 (0.37 to 1.44). CHIP involving DNMT3A (OR, 1.81; 95 % CI, 1.05 to 2.88; <em>P</em> = 0.0193) and ASXL1 (OR, 2.43; 95 % CI, 0.95 to 4.99; <em>P</em> = 0.032) was associated with an increased risk of gastric cancer. These positive associations remained significantly in sensitivity analyses adjusted by known risk factors. Compared to younger individuals and non-CHIP carriers, older participants with CHIP exhibited a significantly higher cumulative incidence of gastric cancer (<em>P</em> < 0.0001).</div></div><div><h3>Conclusions and relevance</h3><div>CHIP is associated with gastric cancer in the elderly and contributes to the positive association between DNM3A and ASXL1 mutations and risk of gastric cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102242"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11713744/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2024.102194
Jinxia Cao, Bin Hu, Tianqi Li, Dan Fang, ling Jiang, Jun Wang
Acute Myeloid Leukemia (AML) is a complex hematological malignancy distinguished by its heterogeneity in genetic aberrations, cellular composition, and clinical outcomes. This diversity complicates the development of effective, universally applicable therapeutic strategies and highlights the necessity for personalized approaches to treatment. In our study, we utilized high-resolution single-cell RNA sequencing from publicly available datasets to dissect the complex cellular landscape of AML. This approach uncovered a diverse array of cellular subpopulations within the bone marrow samples of AML patients. Through meticulous analysis, we identified 156 differentially expressed cytokine-related genes that underscore the nuanced interplay between AML cells and their microenvironment. Leveraging this comprehensive dataset, we constructed a prognostic risk score model based on seven pivotal cytokine-related genes: CCL23, IL2RA, IL3RA, IL6R, INHBA, TNFSF15, and TNFSF18. The mRNA levels of 7 genes in the risk score model have significant different. This model was rigorously validated across several independent AML patient cohorts, showcasing its robust prognostic capability to stratify patients into distinct risk categories. Patients classified under the high-risk category exhibited significantly poorer survival outcomes compared to their low-risk counterparts, underscoring the model's clinical relevance. Additionally, our in-depth investigation into the immune landscape revealed marked differences in immune cell infiltration and cytokine signaling between the identified risk groups, shedding light on potential immune-mediated mechanisms driving disease progression and treatment resistance. This comprehensive analysis not only advances our understanding of the cellular and molecular underpinnings of AML but also introduces a novel, clinically applicable risk score model. This tool holds significant promise for enhancing the precision of prognostic assessments in AML, thereby paving the way for more tailored and effective therapeutic interventions. Our findings represent a pivotal step toward the realization of personalized medicine in the management of AML, offering new avenues for research and treatment optimization in this challenging disease landscape.
{"title":"Cellular heterogeneity and cytokine signatures in acute myeloid leukemia: A novel prognostic model","authors":"Jinxia Cao, Bin Hu, Tianqi Li, Dan Fang, ling Jiang, Jun Wang","doi":"10.1016/j.tranon.2024.102194","DOIUrl":"10.1016/j.tranon.2024.102194","url":null,"abstract":"<div><div>Acute Myeloid Leukemia (AML) is a complex hematological malignancy distinguished by its heterogeneity in genetic aberrations, cellular composition, and clinical outcomes. This diversity complicates the development of effective, universally applicable therapeutic strategies and highlights the necessity for personalized approaches to treatment. In our study, we utilized high-resolution single-cell RNA sequencing from publicly available datasets to dissect the complex cellular landscape of AML. This approach uncovered a diverse array of cellular subpopulations within the bone marrow samples of AML patients. Through meticulous analysis, we identified 156 differentially expressed cytokine-related genes that underscore the nuanced interplay between AML cells and their microenvironment. Leveraging this comprehensive dataset, we constructed a prognostic risk score model based on seven pivotal cytokine-related genes: CCL23, IL2RA, IL3RA, IL6R, INHBA, TNFSF15, and TNFSF18. The mRNA levels of 7 genes in the risk score model have significant different. This model was rigorously validated across several independent AML patient cohorts, showcasing its robust prognostic capability to stratify patients into distinct risk categories. Patients classified under the high-risk category exhibited significantly poorer survival outcomes compared to their low-risk counterparts, underscoring the model's clinical relevance. Additionally, our in-depth investigation into the immune landscape revealed marked differences in immune cell infiltration and cytokine signaling between the identified risk groups, shedding light on potential immune-mediated mechanisms driving disease progression and treatment resistance. This comprehensive analysis not only advances our understanding of the cellular and molecular underpinnings of AML but also introduces a novel, clinically applicable risk score model. This tool holds significant promise for enhancing the precision of prognostic assessments in AML, thereby paving the way for more tailored and effective therapeutic interventions. Our findings represent a pivotal step toward the realization of personalized medicine in the management of AML, offering new avenues for research and treatment optimization in this challenging disease landscape.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102194"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.tranon.2025.102278
Guifang Gan , Xinxia Zhou , Qiaoping Zheng , Xianfu Gao , Xu Chen , Han Zhang , Jinghao Liu , Zhaopeng Shi , Fuxiang Chen
Objectives
The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism.
Materials and methods
The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay.
Results
3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both in vitro and in vivo. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells in vivo and in vitro.
Discussion
3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.
{"title":"3-Hydroxyanthranic acid inhibits growth of oral squamous carcinoma cells through growth arrest and DNA damage inducible alpha","authors":"Guifang Gan , Xinxia Zhou , Qiaoping Zheng , Xianfu Gao , Xu Chen , Han Zhang , Jinghao Liu , Zhaopeng Shi , Fuxiang Chen","doi":"10.1016/j.tranon.2025.102278","DOIUrl":"10.1016/j.tranon.2025.102278","url":null,"abstract":"<div><h3>Objectives</h3><div>The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism.</div></div><div><h3>Materials and methods</h3><div>The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay.</div></div><div><h3>Results</h3><div>3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both <em>in vitro</em> and <em>in vivo</em>. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells <em>in vivo</em> and <em>in vitro</em>.</div></div><div><h3>Discussion</h3><div>3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"52 ","pages":"Article 102278"},"PeriodicalIF":5.0,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11770551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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