Cancer Genetics最新文献_第4页

Study on the anticancer mechanism of hydroxygenkwanin in esophageal cancer via the ESRRA signaling pathway 羟基根宽素通过ESRRA信号通路在食管癌中的抗癌机制研究。

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-26 DOI: 10.1016/j.cancergen.2025.09.011

Yuan Wang , Xin Wan , Yutian Zhang , Jia Qi , Chao Li , Xiaonan Cui

Objective

To explore the role of ESRRA in esophageal squamous cell carcinoma (ESCC) progression and evaluate the antitumor effects of hydroxygenkwanin (HGK), focusing on its interaction with ESRRA and the underlying molecular mechanisms.

Methods

Cell viability, apoptosis, invasion, and proliferation were assessed in EC109 and TE-1 cells treated with HGK using CCK-8, Hoechst staining, Transwell, and colony formation assays. ESRRA expression was analyzed via qPCR and Western blot. An ESCC mouse model was established, with treatment groups receiving HGK. Serum IL-10 and IL-12 levels were measured by ELISA; tumor growth and toxicity were evaluated by histology. EMT marker expression was analyzed by IHC and RT-qPCR. TCGA database analysis explored ESRRA-related pathways and its link to the tumor microenvironment and patient survival.

Results

HGK inhibited EC109 and TE-1 cell proliferation and migration, especially in EC109 cells, by downregulating ESRRA in a dose-dependent manner. In vivo, HGK reduced tumor growth with minimal toxicity, though high doses showed possible renal effects. IL-12 levels decreased, and EMT markers were altered. ESRRA was overexpressed in ESCC tissues and correlated with EMT-related genes. TCGA analysis confirmed ESRRA’s association with poor survival in ESCC patients.

Conclusion

HGK effectively suppresses ESCC with low toxicity, primarily by inhibiting ESRRA and blocking EMT, highlighting its therapeutic potential.

目的：探讨ESRRA在食管鳞状细胞癌（ESCC）进展中的作用，评价羟基根管素（HGK）的抗肿瘤作用，重点研究其与ESRRA的相互作用及其分子机制。方法：采用CCK-8法、Hoechst染色法、Transwell法和集落形成法对HGK处理的EC109和TE-1细胞进行细胞活力、凋亡、侵袭和增殖的评估。通过qPCR和Western blot分析ESRRA的表达。建立ESCC小鼠模型，给药组给予HGK。ELISA法检测血清IL-10、IL-12水平；用组织学方法评价肿瘤的生长和毒性。采用免疫组化（IHC）和RT-qPCR分析EMT标记的表达。TCGA数据库分析探讨了esrra相关通路及其与肿瘤微环境和患者生存的关系。结果：HGK通过下调ESRRA，以剂量依赖性的方式抑制EC109和TE-1细胞的增殖和迁移，特别是在EC109细胞中。在体内，HGK以最小的毒性降低肿瘤生长，尽管高剂量可能会对肾脏产生影响。IL-12水平降低，EMT标志物改变。ESRRA在ESCC组织中过表达，并与emt相关基因相关。TCGA分析证实ESRRA与ESCC患者生存差相关。结论：HGK主要通过抑制ESRRA和阻断EMT对ESCC具有低毒性的有效抑制作用，显示了其治疗潜力。

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引用次数: 0

Molecular mechanisms underlying the oncogenic and tumor-suppressive roles of ZHX2 in cancers 肿瘤中ZHX2的致癌和肿瘤抑制作用的分子机制

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-20 DOI: 10.1016/j.cancergen.2025.09.010

Yifan Wei , Haiyang Guo , Jingjie Zhou , Da Shi, Liqiang Hao

The transcription factor ZHX2 exerts paradoxical roles in cancer, acting as either an oncogene or tumor suppressor in a context-dependent manner. This duality stems from ZHX2’s regulation of key processes including cell cycle, apoptosis, EMT, stemness, and metabolism. Consequently, ZHX2 may impacts tumor cell growth, migration, and immune evasion, positioning it as a promising therapeutic target. This short communication synthesizes current understanding of ZHX2’s molecular structure, transcriptional regulation, and its critical modulation of oncogenic and tumor-suppressive pathways across various cancers. We highlight its potential utility as a prognostic biomarker and its implications for precision medicine, chemotherapy, targeted therapy, and immunotherapy. However, translating ZHX2-targeting strategies faces significant hurdles, particularly concerning tissue-specific restoration and integration with existing treatments. Future research should prioritize overcoming these barriers and exploring ZHX2’s epigenetic regulatory potential.

转录因子ZHX2在癌症中发挥着矛盾的作用，既可以作为致癌基因，也可以作为肿瘤抑制因子。这种双重性源于ZHX2对细胞周期、凋亡、EMT、干性和代谢等关键过程的调控。因此，ZHX2可能影响肿瘤细胞的生长、迁移和免疫逃避，使其成为一个有希望的治疗靶点。这种简短的交流综合了目前对ZHX2分子结构、转录调控及其在各种癌症中致癌和肿瘤抑制途径的关键调控的理解。我们强调其作为预后生物标志物的潜在效用及其对精准医学、化疗、靶向治疗和免疫治疗的影响。然而，转化zhx2靶向策略面临着重大障碍，特别是在组织特异性修复和与现有治疗的整合方面。未来的研究应优先克服这些障碍，探索ZHX2的表观遗传调控潜力。

引用次数: 0

Differential impact of IDH1/2 mutations on outcome in adult acute myeloid leukemia patients IDH1/2突变对成人急性髓性白血病患者预后的差异影响

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-18 DOI: 10.1016/j.cancergen.2025.09.008

Wanfang Yang , Jing Xu , Shuhua Cao , Ning Wang , Zhuanghui Hao , Qing Wang , Yanhong Tan , Xiuhua Chen , Zhifang Xu , Yaofang Zhang , Jianmei Chang , Xiaojuan Wang , Fanggang Ren , Hongwei Wang

Mutations in Isocitrate Dehydrogenase-1 (IDH1) and IDH2 lead to abnormal histone hypermethylation and DNA modifications, disrupting cell differentiation, yet the clinical and prognostic significance of these mutations in primary acute myeloid leukemia (AML) remains debated. This study retrospectively analyzed 181 newly diagnosed AML patients, categorizing them into IDH1mut, IDH2mut, and IDHwt groups to compare clinical features, mutational profiles, and outcomes. IDH1 and IDH2 mutations were detected in 7.7 % (14/181) and 11.6 % (21/181) of cases, respectively. Patients with IDH mutations were older, had higher platelet counts, elevated WT1 mRNA expression, and lower white blood cell counts compared to IDHwt patients. Notably, IDH1mut patients showed no significant OS difference (P = .153), whereas IDH2mut patients exhibited significantly shorter overall survival (OS) than IDHwt patients (HR = 1.844, 95 % CI: 1.008–3.792, P = .047). Additionally, IDH1mut patients with DNMT3A co-mutations also demonstrated shorter DFS and OS (P = .013 and P = .003, respectively), while IDH2mut patients with co-mutations in NPM1, ASXL1, or SRSF2 had reduced disease-free survival (DFS) and OS (P < .05).

These findings suggest that early detection of IDH1/2 mutations and associated clinical features at AML diagnosis could provide a rationale for targeted therapy with IDH inhibitors, potentially improving patient outcomes.

异柠檬酸脱氢酶-1 （IDH1）和IDH2突变导致异常组蛋白超甲基化和DNA修饰，破坏细胞分化，但这些突变在原发性急性髓性白血病（AML）中的临床和预后意义仍存在争议。本研究回顾性分析了181例新诊断的AML患者，将他们分为IDH1mut、IDH2mut和IDHwt组，比较临床特征、突变谱和结局。IDH1和IDH2突变分别占7.7%（14/181）和11.6%（21/181）。与IDHwt患者相比，IDH突变患者年龄较大，血小板计数较高，WT1 mRNA表达升高，白细胞计数较低。值得注意的是，IDH1mut患者的总生存期（OS）无显著差异（P = 0.153），而IDH2mut患者的总生存期（OS）明显短于IDHwt患者（HR = 1.844, 95% CI: 1.008-3.792, P = 0.047）。此外，DNMT3A共突变的IDH1mut患者的DFS和OS也较短（P = 0.013和P = 0.003），而NPM1、ASXL1或SRSF2共突变的IDH2mut患者的无病生存期（DFS）和OS较低（P < 0.05）。这些发现表明，在AML诊断中早期检测IDH1/2突变和相关临床特征可以为IDH抑制剂靶向治疗提供理论依据，可能改善患者的预后。

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引用次数: 0

Comparison of somatic variant oncogenicity classification using ClinGen/CGC/VICC guidelines and QIAGEN Clinical Insight Interpret decision support software 使用ClinGen/CGC/VICC指南和QIAGEN临床洞察解释决策支持软件进行体细胞变异致癌性分类的比较

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-18 DOI: 10.1016/j.cancergen.2025.09.009

Aarthi Goverdhan , Lisa Mullineaux , Amber Pryzbylski , Claire Teigen , Kevin C. Halling , Sheryl K. Elkin , Beth A. Pitel

Accurate clinical interpretation of somatic cancer variants is critical for diagnosis and guidance of precision oncology treatment. As the depth and breadth of genomic sequencing increased, laboratories developed independent standards for the classification of somatic variants. In response, a set of standards for classification were published by a collaboration among Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC) and Variant Interpretation for Cancer Consortium (VICC). This study evaluated these standards and compared the resulting classifications to the classifications generated by a clinical decision support software system, QIAGEN Clinical Insight (QCI) Interpret One, a system using a version of the 2015 consensus guidelines by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) customized for somatic assessment. The published variant set for validation was utilized and expanded by conducting a retrospective analysis using real-world cancer variants drawn from oncology cases tested at Mayo Clinic. For “oncogenic” and “likely oncogenic” variants in the combined datasets, automated classifications by the QCI system were 97.2% concordant with those assessed using the ClinGen/CGC/VICC system. The ClinGen/CGC/VICC standards led to more conservative variant classifications, with a larger proportion of variants assigned to the “variant of unknown significance” and “likely benign” designations. This study demonstrates that the ClinGen/CGC/VICC guidelines and clinical decision support tools can be effectively used together to facilitate somatic variant classification and interpretation.

准确的临床解释体细胞癌变异是诊断和指导精确肿瘤治疗的关键。随着基因组测序的深度和广度的增加，实验室开发了独立的体细胞变异分类标准。为此，临床基因组资源（ClinGen）、癌症基因组学联盟（CGC）和癌症变异解释联盟（VICC）合作发布了一套分类标准。本研究对这些标准进行了评估，并将结果分类与临床决策支持软件系统QIAGEN clinical Insight (QCI) Interpret One生成的分类进行了比较，该系统使用了美国医学遗传学学院（ACMG）和分子病理学协会（AMP）为体细胞评估定制的2015年共识指南版本。通过对梅奥诊所测试的肿瘤病例中提取的真实癌症变异进行回顾性分析，利用并扩展了已发表的用于验证的变异集。对于合并数据集中的“致癌”和“可能致癌”变异，QCI系统的自动分类与使用ClinGen/CGC/VICC系统评估的结果一致性为97.2%。ClinGen/CGC/VICC标准导致了更保守的变体分类，更大比例的变体被分配到“未知意义的变体”和“可能良性的”名称。本研究表明，ClinGen/CGC/VICC指南和临床决策支持工具可以有效地结合使用，以促进体细胞变异的分类和解释。

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引用次数: 0

The multidimensional role of laminin γ2 (LAMC2) on cancer progression 层粘连蛋白γ - 2 （LAMC2）在癌症进展中的多维作用

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-16 DOI: 10.1016/j.cancergen.2025.09.007

Xiaojuan Zhang , Juan Xie , Tao Fu , Zhen Gao , Hengrui Liu , Zhenshan Yang

Laminin, a critical component of the basement membrane, plays an indispensable role in numerous biological processes. Among its subunits, laminin γ2 (LAMC2) emerges as a key player in the progression of cancer. This review delves into the current understanding of LAMC2′s role, highlighting its significant contribution to cancer development through promoting cell proliferation, invasion, and vasculogenic mimicry, as well as inhibiting apoptosis. Notably, LAMC2 expression is markedly increased in cancerous tissues compared to normal counterparts, with higher levels of LAMC2 correlating with poorer survival rates. This correlation underscores LAMC2′s potential as a diagnostic and prognostic marker across various cancers. Furthermore, the increasing importance of LAMC2 as a viable target for cancer therapy is explored. This review aims to provide a thorough overview of LAMC2′s involvement in cancer progression, prognostic implications, potential therapeutic target, and involved signaling pathway, and to outline future research directions in this promising field.

层粘连蛋白是基底膜的重要组成部分，在许多生物过程中起着不可或缺的作用。在其亚基中，层粘连蛋白γ - 2 （LAMC2）在癌症的进展中起着关键作用。这篇综述深入了目前对LAMC2作用的理解，强调了它通过促进细胞增殖、侵袭和血管生成模拟以及抑制细胞凋亡对癌症发展的重要贡献。值得注意的是，与正常组织相比，LAMC2在癌组织中的表达明显增加，LAMC2水平越高，生存率越低。这种相关性强调了LAMC2作为各种癌症的诊断和预后标志物的潜力。此外，LAMC2作为一种可行的癌症治疗靶点的重要性日益增加。本文旨在全面综述LAMC2在癌症进展中的作用、预后意义、潜在的治疗靶点和涉及的信号通路，并概述这一前景广阔的领域的未来研究方向。

引用次数: 0

Galectin-9 promotes colon cancer development by polarizing macrophages toward the M2 phenotype 半凝集素-9通过使巨噬细胞向M2表型极化促进结肠癌的发展

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-10 DOI: 10.1016/j.cancergen.2025.09.006

Jun Zhang , Yang Xu , Xiao Han , Yan Gao , Zhanbo Wei , Xu Sun

Galectin-9 plays multiple roles in various tumors and exerts immune regulation within the tumor microenvironment. It is closely associated with tumor prognosis. This study aimed to analyze the expression of galectin-9 in the colon tumor microenvironment. The results indicated that galectin-9 expression is higher in the colon tumor microenvironment compared to adjacent normal tissues. Furthermore, high expression of galectin-9 was related to M2-type macrophages, which promote tumor development by increasing tumor cell viability, migration, and invasion. Notably, high expression of galectin-9 in colon tumor microenvironment contributed to the polarization of M2 cells, marked by high expression of arginase-1, CD163, and IL-10 and low expression of iNOS. When M0 macrophages were treated with galectin-9 and co-cultured with colon cancer cell lines, it resulted in increased cancer cell growth, migration, and invasion by promoting the differentiation of THP-1 monocytes into the M2 macrophages. The specific mechanism by which galectin-9 promotes M2 polarization involves its binding to Tim-3, recruiting PI3K-p85 to the cytoplasmic domain of Tim-3. This interaction further affects the PI3K/Akt signal pathway, leading to M2 polarization.

半乳糖凝集素-9在多种肿瘤中发挥多种作用，在肿瘤微环境中发挥免疫调节作用。它与肿瘤预后密切相关。本研究旨在分析半乳糖凝集素-9在结肠肿瘤微环境中的表达。结果表明，半凝集素-9在结肠肿瘤微环境中的表达高于邻近正常组织。此外，半乳糖凝集素-9的高表达与m2型巨噬细胞有关，其通过增加肿瘤细胞的活力、迁移和侵袭来促进肿瘤的发展。值得注意的是，在结肠肿瘤微环境中，半乳糖凝集素-9的高表达促进了M2细胞的极化，表现为精氨酸酶-1、CD163、IL-10的高表达和iNOS的低表达。M0巨噬细胞经半凝集素-9处理后与结肠癌细胞系共培养，通过促进THP-1单核细胞向M2巨噬细胞的分化，促进癌细胞的生长、迁移和侵袭。半乳糖凝集素-9促进M2极化的具体机制包括其与Tim-3结合，将PI3K-p85招募到Tim-3的细胞质结构域。这种相互作用进一步影响PI3K/Akt信号通路，导致M2极化。

{"title":"Galectin-9 promotes colon cancer development by polarizing macrophages toward the M2 phenotype","authors":"Jun Zhang , Yang Xu , Xiao Han , Yan Gao , Zhanbo Wei , Xu Sun","doi":"10.1016/j.cancergen.2025.09.006","DOIUrl":"10.1016/j.cancergen.2025.09.006","url":null,"abstract":"<div><div>Galectin-9 plays multiple roles in various tumors and exerts immune regulation within the tumor microenvironment. It is closely associated with tumor prognosis. This study aimed to analyze the expression of galectin-9 in the colon tumor microenvironment. The results indicated that galectin-9 expression is higher in the colon tumor microenvironment compared to adjacent normal tissues. Furthermore, high expression of galectin-9 was related to M2-type macrophages, which promote tumor development by increasing tumor cell viability, migration, and invasion. Notably, high expression of galectin-9 in colon tumor microenvironment contributed to the polarization of M2 cells, marked by high expression of arginase-1, CD163, and IL-10 and low expression of iNOS. When M0 macrophages were treated with galectin-9 and co-cultured with colon cancer cell lines, it resulted in increased cancer cell growth, migration, and invasion by promoting the differentiation of THP-1 monocytes into the M2 macrophages. The specific mechanism by which galectin-9 promotes M2 polarization involves its binding to Tim-3, recruiting PI3K-p85 to the cytoplasmic domain of Tim-3. This interaction further affects the PI3K/Akt signal pathway, leading to M2 polarization.</div></div>","PeriodicalId":49225,"journal":{"name":"Cancer Genetics","volume":"298 ","pages":"Pages 141-150"},"PeriodicalIF":2.1,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145158112","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}

引用次数: 0

Development and multi-cohort validation of a prognostic risk score model for oral squamous cell carcinoma based on a three-gene signature 基于三基因标记的口腔鳞状细胞癌预后风险评分模型的开发和多队列验证

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-05 DOI: 10.1016/j.cancergen.2025.09.005

Junxu Chen , Dongwook Kim , Jae Young Kim , Hyung Jun Kim

Background

Oral squamous cell carcinoma (OSCC) carries substantial mortality despite surgery-based management. Reliable biomarkers and practical prognostic tools are needed to guide individualized care.

Methods

Transcriptomic and clinical data from TCGA and multiple GEO cohorts were integrated. Candidate genes identified by differential expression analysis, WGCNA, and PPI were refined using LASSO and Random Forest, then entered a multivariable Cox model to derive a three-gene risk score. Performance was assessed with Kaplan–Meier curves, time-dependent ROC, and calibration, and validated across internal, external, and combined datasets. Expression was examined by RT-qPCR and Western blot in OSCC and normal oral cell lines. Immune infiltration and pathway enrichment analyses were conducted to contextualize biology.

Results

The three-gene signature (CXCL12, PLAU, PXDN) separated risk groups in the training cohort with 1/3/5-year AUCs of 0.767/0.625/0.714. In three independent external cohorts, high-risk patients consistently had worse overall survival (log-rank p = 0.0092, ≤0.0001, ≤0.0001), with time-AUC ranges of 0.581–0.747 (1-year), 0.555–0.795 (3-year), and 0.603–0.812 (5-year). In TCGA, the score remained prognostic across sex, age, smoking, drinking, and stage III/IV subgroups (all p ≤ 0.05), with a consistent trend in stage I/II (p = 0.09). A nomogram integrating clinical variables with the risk score achieved a C-index of 0.63 with good 1–5-year calibration and outperformed TNM staging alone (C-index 0.63 vs 0.58; 95 % CI 0.58–0.70 vs 0.54–0.61). RT-qPCR/Western blot confirmed consistent differential expression of all three biomarkers. Immune-infiltration and pathway analyses revealed distinct microenvironmental and molecular features across risk strata.

Conclusion

We present a robust, externally validated three-gene prognostic model for OSCC, supported by experimental evidence and superior to TNM staging for discrimination, offering a practical nomogram for individualized risk estimation from 1 to 5 years.

背景：尽管手术治疗，口腔鳞状细胞癌（OSCC）的死亡率仍然很高。需要可靠的生物标志物和实用的预后工具来指导个体化护理。方法整合来自TCGA和多个GEO队列的转录组学和临床数据。通过差异表达分析、WGCNA和PPI鉴定的候选基因使用LASSO和Random Forest进行细化，然后进入多变量Cox模型，得出三基因风险评分。通过Kaplan-Meier曲线、随时间变化的ROC曲线和校准进行评估，并通过内部、外部和联合数据集进行验证。用RT-qPCR和Western blot检测OSCC和正常口腔细胞株的表达。免疫浸润和途径富集分析进行了背景生物学。结果三基因标记（CXCL12， PLAU， PXDN）分离了训练队列的风险组，1/3/5年auc为0.767/0.625/0.714。在三个独立的外部队列中，高危患者的总生存率均较差（log-rank p = 0.0092,≤0.0001,≤0.0001），时间auc范围为0.581-0.747（1年），0.555-0.795（3年）和0.603-0.812（5年）。在TCGA中，评分在性别、年龄、吸烟、饮酒和III/IV期亚组中仍具有预测作用（均p≤0.05），在I/II期中趋势一致（p = 0.09）。综合临床变量和风险评分的nomogram C-index为0.63，具有良好的1 - 5年校准效果，优于单纯的TNM分期（C-index 0.63 vs 0.58; 95% CI 0.58 - 0.70 vs 0.54-0.61）。RT-qPCR/Western blot证实了这三种生物标志物的一致差异表达。免疫浸润和途径分析揭示了不同风险层的微环境和分子特征。结论我们提出了一个可靠的、外部验证的OSCC三基因预后模型，该模型有实验证据支持，在区分方面优于TNM分期，为1 - 5年的个体化风险估计提供了一个实用的nomogram。

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引用次数: 0

A pilot study of evaluation of a deep-learning-based homologous recombination deficiency assay in korean patients with ovarian high-grade serous carcinoma: Diagnostic performance and clinical implications 一项评估基于深度学习的同源重组缺陷测定在韩国卵巢高级别浆液性癌患者中的初步研究：诊断性能和临床意义

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-04 DOI: 10.1016/j.cancergen.2025.09.003

Gui Young Kwon , Sanghoo Lee , Jeonghoon Hong , Yiseul Kim , Hee-Ji Choi , Jihye Yun , Jinhee Park , Jiyoon Jung , Joonsung Yoon , SaeYun Baik , Mi-Kyeong Lee , Kyoung-Ryul Lee , Jeong Won Kim

Background

Homologous recombination deficiency (HRD)-related genetic mutations in ovarian high-grade serous carcinoma (HGSC) are known to be ethnic specific. Here, we assessed the diagnostic performance of HRD and its clinical implication in Korean HGSC patients using the SOPHiA DDM HRD Solution.

Methods

Sixty-three ovarian cancer (OC) patients were enrolled, including 53 with HGSC and 10 with other subtypes. HRD status was determined by 28 homologous recombination repair (HRR) genetic sequencing and genomic scarring (GS) measurement. The GS was measured through low-pass whole-genome sequencing and quantified using the genomic integrity index (GII).

Results

HRD status was analyzed in 53 out of 63 OC patients (84.1 %). Among the 53 with HGSC, HRD results were available for 83.0 % (n = 44). Of these HGSC patients, 72.7 % (n = 32) were HRD-positive, including 15 with BRCA1/2 mutations (34.1 %) and 27 with GI-positive (61.4 %). In HGSC, HRD-positive status was associated with solid, pseudoendometrioid or transitional (SET) pattern (P = 0.015). Patients with positive HRD and high GII (>4.2) exhibited improved disease-free survival (DFS) and overall survival (OS) compared to those with negative HRD (P = 0.003 and 0.024, respectively) and low GII (P < 0.001 and P = 0.006, respectively). Multivariate analysis revealed a high GII as a better prognostic indicator for DFS and OS (P = 0.003 and 0.032, respectively).

Conclusion

The HRD assay offers high diagnostic performance of HRD in Korean OC patients. Furthermore, the prognostic value of high GII and HRD, as well as an association with SET pattern and HRD was evident in HGSC.

背景：已知卵巢高级别浆液性癌（HGSC）中同源重组缺陷（HRD）相关基因突变具有种族特异性。在这里，我们使用SOPHiA DDM HRD溶液评估韩国HGSC患者HRD的诊断性能及其临床意义。方法纳入63例卵巢癌（OC）患者，其中HGSC 53例，其他亚型10例。通过28个同源重组修复（HRR）基因测序和基因组疤痕（GS）测量来确定HRD状态。GS通过低通全基因组测序测量，并使用基因组完整性指数（GII）进行量化。结果63例OC患者中有53例（84.1%）存在shrd状况。在53例HGSC患者中，HRD结果为83.0% （n = 44）。在这些HGSC患者中，72.7% （n = 32）为hdd阳性，包括15例BRCA1/2突变（34.1%）和27例gi阳性（61.4%）。在HGSC中，hrd阳性状态与实性、假子宫内膜样或移行性（SET）模式相关（P = 0.015）。与HRD阴性患者（P = 0.003和0.024）和低GII患者（P <； 0.001和P = 0.006）相比，HRD阳性和高GII患者（>4.2）表现出更好的无病生存（DFS）和总生存（OS）。多因素分析显示，高GII是DFS和OS更好的预后指标（P分别= 0.003和0.032）。结论HRD检测对韩国OC患者的HRD有较高的诊断价值。此外，高GII和HRD的预后价值，以及与SET模式和HRD的关联在HGSC中是明显的。

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引用次数: 0

Hi-C analysis of amplification of MYC, PVT1, and CCDC26 on marker chromosomes in the NB-4 cell line NB-4细胞系标记染色体上MYC、PVT1和CCDC26基因扩增的Hi-C分析

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-03 DOI: 10.1016/j.cancergen.2025.09.004

Tetsuko Kobayashi , Satsuki Matsushima , Hiroaki Ohnishi

MYC proto-oncogene may be amplified ectopically in acute myeloid leukemia (AML) as extrachromosomal DNA (ecDNA) such as double minutes (dmins). However, the mechanism and location of MYC amplification have not been fully elucidated. To characterize the location of MYC and its surrounding structure in NB-4 cells, we conducted this study using in situ high-throughput chromosomal conformation capture (in situ Hi-C). Hi-C analysis was performed in NB-4 cell line. Whole genome sequencing (WGS) and fluorescence in situ hybridization (FISH) were used for confirmation. Hi-C revealed an inversion involving PVT1 and CCDC26 and amplified segments involving MYC, PVT1, and CCDC26 on 8q24.21 region. MYC, PVT1, and CCDC26 were found not only on chromosome 8, but also somewhere intranuclear, other than on chromosome 8. Karyotyping revealed only two normal chromosomes 8, and the others were missing or abnormal. FISH revealed the presence of MYC, PVT1, and CCDC26 on the two normal chromosomes 8 and multiple marker chromosomes. Our results suggest that the numerical and structural abnormalities of chromosome 8 precede MYC amplification and moving. MYC may have properties that move not only to dmins, but also to other chromosomes such as marker chromosomes for unknown but certain reasons. MYC ectopic amplification is not only a phenomenon in solid tumors, but also a recurrent phenomenon in AML. Furthermore, in a broader sense, ectopic amplification is a form of abnormal oncogenes. We propose Hi-C as a screening method for this phenomenon. We will further verify this phenomenon in various phases of multiple AML cell lines and patient samples.

MYC原癌基因可能在急性髓性白血病（AML）中异位扩增，表现为染色体外DNA (ecDNA)，如双分钟（dmins）。然而，MYC扩增的机制和位置尚未完全阐明。为了表征NB-4细胞中MYC的位置及其周围结构，我们使用原位高通量染色体构象捕获（in situ Hi-C）进行了这项研究。NB-4细胞株进行Hi-C分析。采用全基因组测序（WGS）和荧光原位杂交（FISH）进行验证。Hi-C在8q24.21区域发现了涉及PVT1和CCDC26的倒置和涉及MYC、PVT1和CCDC26的扩增片段。MYC、PVT1和CCDC26不仅在8号染色体上发现，而且在核内的某些地方也发现，而不是在8号染色体上。核型分析显示只有两条正常染色体8，其他染色体缺失或异常。FISH发现MYC、PVT1和CCDC26存在于两条正常染色体8和多条标记染色体上。我们的研究结果表明，8号染色体的数量和结构异常先于MYC扩增和移动。MYC可能具有不仅移动到dmins的特性，而且由于未知但确定的原因也移动到其他染色体，如标记染色体。MYC异位扩增不仅是实体瘤的现象，也是AML的复发现象。此外，在更广泛的意义上，异位扩增是异常癌基因的一种形式。我们提出Hi-C作为这种现象的筛选方法。我们将在多个AML细胞系和患者样本的不同阶段进一步验证这一现象。

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引用次数: 0

Exploring replication stress and cellular senescence as key targets in novel cancer therapies 探索复制应激和细胞衰老作为新型癌症治疗的关键靶点

IF 2.1 4区医学 Q4 GENETICS & HEREDITY

Cancer Genetics

Pub Date : 2025-09-02 DOI: 10.1016/j.cancergen.2025.09.002

Suman Kumar Ray, Sukhes Mukherjee

The hallmark features most commonly found in human cancers include sustained cell proliferation, evasion of apoptosis, and genetic instability. Replication stress, which contributes to genome instability and is characteristic of both pre-cancerous and cancerous cells, arises from conditions that cause significant DNA damage. DNA replication is a highly controlled process in each cell cycle, ensuring accurate duplication of DNA for distribution to daughter cells. Cellular senescence prevents damaged or aging cells from dividing by halting their progression through the cell cycle. Senescent cells undergo a variety of changes, such as metabolic shifts, chromatin alterations, and autophagy regulation. Senescence can be triggered by telomere shortening, leading to a limited number of cell divisions (replicative senescence), or by oncogene overexpression, which functions as a mechanism to protect against cancer. A number of activated oncogenes have been shown to induce replication stress, a crucial early step in the development of cancer. Investigating the mechanisms behind the replication stress response may open up new avenues for cancer therapies, including small-molecule inhibitors targeting pathways such as Chk1, TLK, WEE1, ATR, MELK, PARP, NAE, and others. This review examines the relationship between persistent replication stress and cellular senescence in carcinogenesis, aiming to provide insights into the early stages of oncogenesis and to inform the development of new cancer diagnostic and therapeutic strategies.

在人类癌症中最常见的标志特征包括持续的细胞增殖，逃避凋亡和遗传不稳定。复制压力导致基因组不稳定，是癌前细胞和癌细胞的特征，它产生于导致显著DNA损伤的条件。在每个细胞周期中，DNA复制是一个高度控制的过程，确保准确复制DNA以分配给子细胞。细胞衰老通过停止细胞周期的进程来防止受损或老化的细胞分裂。衰老细胞经历多种变化，如代谢变化、染色质改变和自噬调节。衰老可由端粒缩短引发，导致细胞分裂数量有限（复制性衰老），或由癌基因过度表达引发，这是一种预防癌症的机制。许多被激活的致癌基因已被证明可以诱导复制应激，这是癌症发展的关键早期步骤。研究复制应激反应背后的机制可能为癌症治疗开辟新的途径，包括靶向Chk1、TLK、WEE1、ATR、MELK、PARP、NAE等途径的小分子抑制剂。本文综述了肿瘤发生过程中持续复制应激与细胞衰老之间的关系，旨在为肿瘤发生的早期阶段提供见解，并为新的癌症诊断和治疗策略的发展提供信息。

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