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SOX11 as a potential prognostic biomarker in hepatocellular carcinoma linked to immune infiltration and ferroptosis. SOX11作为肝细胞癌潜在的预后生物标志物与免疫浸润和铁变态反应有关。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.03
Hongyu Chen, Qiangguo Ao, Yueling Wang, Yue Qian, Qingli Cheng, Wei Zhang

Objective: SOX11 is expressed in numerous malignancies, including hepatocellular carcinomas (HCC), but its oncogenic function has not been elucidated. Here, we performed a comprehensive bioinformatics analysis of the Liver Hepatocellular Carcinoma (LIHC) dataset to investigate the function of SOX11 in tumorgenesis.

Methods: SOX11 expression data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were validated by immunohistochemistry (IHC). Co-expression, differential expression, and functional analyses utilized TCGA-LIHC, Timer 2.0, Metascape, GTEx, and LinkedOmics databases. Associations with immune infiltration, ferroptosis, and immune checkpoint genes were assessed. Genetic changes were explored via CBioPortal. Logistic regression, receiver operating characteristic curve (ROC), Kaplan-Meier analysis, and nomogram modeling evaluated associations with HCC clinicopathological features. SOX11's impact on proliferation and migration was studied in HepG2 and HuH7 cell lines.

Results: SOX11 was significantly elevated in HCC tumors compared to controls. SOX11-associated genes exhibited differential expression in pathways involving extracellular membrane ion channels. Significant associations were found between SOX11 levels, immune infiltration, ferroptosis, and immune checkpoint genes in HCC tissue. SOX11 levels correlated with HCC stage, histologic grade, and tumor status, and independently predicted overall and disease-specific survival. SOX11 expression effectively distinguished between tumor and normal liver tissue. Spearman correlations highlighted a significant relationship between SOX11 and ferroptosis-associated genes. Decreased SOX11 levels in HepG2 and HuH7 cells resulted in reduced proliferation and migration.

Conclusions: SOX11 was found to represent a promising biomarker within HCC diagnosis and prognosis together with being a possible drug-target.

目的:SOX11在包括肝细胞癌(HCC)在内的多种恶性肿瘤中均有表达,但其致癌功能尚未阐明。在此,我们对肝细胞癌(LIHC)数据集进行了全面的生物信息学分析,以研究SOX11在肿瘤发生中的功能:通过免疫组化(IHC)验证了癌症基因组图谱(TCGA)和基因表达总库(GEO)中的SOX11表达数据。共表达、差异表达和功能分析利用了TCGA-LIHC、Timer 2.0、Metascape、GTEx和LinkedOmics数据库。评估了与免疫浸润、铁突变和免疫检查点基因的关联。通过 CBioPortal 对基因变化进行了研究。逻辑回归、接收者操作特征曲线(ROC)、Kaplan-Meier分析和提名图模型评估了与HCC临床病理特征的关联。在 HepG2 和 HuH7 细胞系中研究了 SOX11 对增殖和迁移的影响:结果:与对照组相比,SOX11在HCC肿瘤中明显升高。SOX11相关基因在涉及细胞外膜离子通道的通路中表现出不同的表达。在 HCC 组织中,SOX11 水平、免疫浸润、铁变态反应和免疫检查点基因之间存在显著关联。SOX11水平与HCC分期、组织学分级和肿瘤状态相关,并能独立预测总生存期和疾病特异性生存期。SOX11 的表达能有效区分肿瘤和正常肝组织。斯皮尔曼相关性强调了SOX11与铁蛋白沉积相关基因之间的重要关系。HepG2和HuH7细胞中SOX11水平的降低导致增殖和迁移能力下降:结论:研究发现 SOX11 是诊断 HCC 和预后的一种有前途的生物标记物,同时也是一种可能的药物靶点。
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引用次数: 0
A pilot clinical study to evaluate feasibility of using single patient classifier as a prognostic test in stage II-III gastric cancer patients. 一项试点临床研究,评估将单个患者分类器用作 II-III 期胃癌患者预后检测的可行性。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.02
Ji Yeong An, Sung Eun Oh, Soomin Ahn, Hyoung-Ii Kim, Yoo Min Kim, Minah Cho, Keun Won Ryu, Hong Man Yoon, Young Kyu Park, In Gyu Kwon, Sung Hoon Noh, Kyung Hee Lee, In Cho, Myoung Won Son, Jong Won Kim, Young-Woo Kim

Objective: Precision medicine approaches emphasize the importance of reliable prognostic tools for guiding individualized therapy decisions. In this study, we evaluated the clinical feasibility of the single patient classifier (SPC) test, a new clinical-grade prognostic assay, in stage II-III gastric cancer patients.

Methods: A prospective multicenter study was conducted, involving 237 patients who underwent gastrectomy between September 2019 and August 2020 across nine hospitals. The SPC test was employed to stratify patients into risk groups, and its feasibility and performance were evaluated. The primary endpoint was the proportion of the cases in which the test results were timely delivered before selecting postoperative treatment. Furthermore, 3-year disease-free survivals of risk groups were analyzed.

Results: The SPC test met the primary endpoint criteria. The 99.5% of SPC tests were timely delivered to hospitals before the postoperative treatment started. In a clinical setting, the median time from the specimen transfer to laboratory to the result delivery to hospital was 4 d. Furthermore, 3-year disease-free survivals were significantly different between risk groups classified with SPC tests.

Conclusions: This study highlights the SPC test's feasibility in offering crucial information timely delivered for making informed decisions regarding postoperative treatment strategies. It also provides evidence to support the implementation of a future prospective clinical trial aimed at evaluating the clinical utility of the SPC test in guiding personalized treatment decisions for gastric cancer patients.

目的:精准医疗方法强调可靠的预后工具对于指导个体化治疗决策的重要性。在这项研究中,我们评估了单个患者分类器(SPC)测试的临床可行性,这是一种新的临床级预后检测方法,适用于II-III期胃癌患者:开展了一项前瞻性多中心研究,涉及9家医院在2019年9月至2020年8月期间接受胃切除术的237名患者。采用 SPC 检验对患者进行风险分层,并评估其可行性和性能。主要终点是在选择术后治疗前及时得到检测结果的病例比例。此外,还对风险组的 3 年无病生存率进行了分析:结果:SPC检测符合主要终点标准。99.5%的 SPC 检测结果在术后治疗开始前及时送达医院。在临床环境中,从标本转移到实验室到结果送达医院的中位时间为4 d。此外,通过SPC检验划分的风险组别之间的3年无病生存率有显著差异:本研究强调了 SPC 检验的可行性,它能及时提供关键信息,以便就术后治疗策略做出明智的决定。该研究还为未来开展前瞻性临床试验提供了证据支持,该试验旨在评估 SPC 检验在指导胃癌患者个性化治疗决策方面的临床实用性。
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引用次数: 0
Neoadjuvant chemotherapy with capecitabine combined with oxaliplatin for mid-low locally advanced rectal cancer with negative mesorectal fascia: Long-term outcomes of a prospective trial (PKUCH-R03 trial). 卡培他滨联合奥沙利铂新辅助化疗治疗直肠中膜筋膜阴性的中低位局部晚期直肠癌:一项前瞻性试验(PKUCH-R03 试验)的长期结果。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.05
Nan Chen, Minghe Zhao, Yunfeng Yao, Lin Wang, Yifan Peng, Tingting Sun, Tiancheng Zhan, Jun Zhao, Aiwen Wu

Objective: To evaluate the safety and efficacy of neoadjuvant chemotherapy (NCT) in mid-low locally advanced rectal cancer with negative mesorectal fascia (MRF).

Methods: This prospective, single-arm phase II trial was designed and conducted at Peking University Cancer Hospital. The patients who provided consent received 3 months of NCT (capecitabine and oxaliplatin, CapOX) followed by total mesorectal excision (TME). The primary endpoint was the rate of pathological complete response (pCR).

Results: From January 2019 through December 2021, a total of 53 patients were enrolled, 7.5% of whom experienced grade 3-4 adverse events during NCT. The pCR rate was 17.0% for the entire cohort, and the overall rate of postoperative complications was 37.7% (1.9% of grade IIIa patients). The 3-year disease-free survival rate was 91.4%, and 23.5% (12/51) of the patients suffered from major low anterior resection syndrome (LARS). Postoperative complications were independently associated with major LARS.

Conclusions: For patients with mid-low rectal cancer with negative MRF, 3 months of NCT were found to yield a favorable tumor response with acceptable toxicity. With fair long-term survival, the NCT regimen could be associated with low rates of perioperative complications as well as acceptable anal function.

目的评估新辅助化疗(NCT)对直肠系膜筋膜(MRF)阴性的中低位局部晚期直肠癌的安全性和有效性:这项前瞻性单臂 II 期试验由北京大学肿瘤医院设计和实施。征得同意的患者接受 3 个月的 NCT(卡培他滨和奥沙利铂,CapOX)治疗,然后进行全直肠系膜切除术(TME)。主要终点是病理完全反应率(pCR):从2019年1月到2021年12月,共有53名患者入组,其中7.5%的患者在NCT期间出现了3-4级不良事件。整个队列的病理完全反应率为17.0%,术后并发症总发生率为37.7%(IIIa级患者占1.9%)。3年无病生存率为91.4%,23.5%(12/51)的患者患有严重的低位前切除综合征(LARS)。术后并发症与严重低位前切除综合征密切相关:结论:对于MRF阴性的中低位直肠癌患者,3个月的NCT可产生良好的肿瘤反应,且毒性可接受。在长期生存率尚可的情况下,NCT疗法的围手术期并发症发生率低,肛门功能也可接受。
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引用次数: 0
Potential value of detection of minimal residual disease in colorectal cancer following radical resection. 检测根治性切除术后大肠癌最小残留病灶的潜在价值。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.07
Wenji Pu, Fang Chen, Yuan Tang, Yanling Qu, Yunzhu Han, Jiandong Zha, Jing Jin, Fengming Kong

Although there has been significant advancement in the identification and management of colorectal cancer (CRC) in recent years, there is still room for improvement in the current standard treatment regimen. One area of concern is the lack of reliable tumor markers to predict treatment efficacy and guide tailored care. Due to its dynamic, effective, and non-invasive benefits over tissue biopsy, the detection of minimal or molecular residual lesions (MRD) based on circulating tumor DNA (ctDNA) is beneficial to the clinical development of drugs for patients with CRC after radical treatment, as well as for continuous monitoring of tumor recurrence and malignancy molecular gene evolution. The detection of ctDNA can currently be used to guide individual postoperative auxiliary treatment decisions (upgrade or downgrade treatment) in CRC, stratify the risk of clinical recurrence more precisely, and predict the risk of recurrence in advance of imaging examination, according to a large number of observational or prospective clinical studies. With increasing clarity comes the possibility of selecting a regimen of treatment based on postoperative ctDNA, which also improves the accuracy of clinical recurrence risk assessment for CRC. Therefore, it is anticipated that the identification of ctDNA would alter the current framework for dealing with CRC and lead to individualized, stratified precision therapy; however, additional confirmation will require subsequent high-quality, prospective, large-scale randomized controlled studies. This article will provide an overview of the definition and clinical significance of MRD, the primary indications and technological challenges for MRD detection, along with the advancement in clinical research about ctDNA detection following radical resection of the CRC.

尽管近年来在结直肠癌(CRC)的识别和管理方面取得了重大进展,但目前的标准治疗方案仍有改进的余地。其中一个值得关注的问题是缺乏可靠的肿瘤标志物来预测治疗效果和指导有针对性的治疗。与组织活检相比,基于循环肿瘤 DNA(ctDNA)的微小或分子残留病灶(MRD)检测具有动态、有效和无创的优点,有利于对根治性治疗后的 CRC 患者进行药物临床开发,也有利于对肿瘤复发和恶性肿瘤分子基因演变进行持续监测。根据大量的观察性或前瞻性临床研究,ctDNA 的检测目前可用于指导 CRC 患者的术后辅助治疗决策(升级或降级治疗),更精确地对临床复发风险进行分层,并在影像学检查前预测复发风险。随着ctDNA越来越清晰,根据术后ctDNA选择治疗方案的可能性也越来越大,这也提高了CRC临床复发风险评估的准确性。因此,可以预见,ctDNA 的鉴定将改变目前处理 CRC 的框架,并带来个体化、分层的精准治疗;不过,进一步的确认还需要后续的高质量、前瞻性、大规模随机对照研究。本文将概述 MRD 的定义和临床意义、MRD 检测的主要适应症和技术挑战,以及有关 CRC 根治性切除术后 ctDNA 检测的临床研究进展。
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引用次数: 0
Immune status and combined immunotherapy progression in Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. 克氏鼠肉瘤病毒癌基因同源体(KRAS)突变肿瘤的免疫状态和联合免疫疗法的进展。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.06
Dongsheng He, Rilan Bai, Naifei Chen, Jiuwei Cui

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene, occurring in various tumor types. Despite extensive efforts over the past 40 years to develop inhibitors targeting KRAS mutations, resistance to these inhibitors has eventually emerged. A more precise understanding of KRAS mutations and the mechanism of resistance development is essential for creating novel inhibitors that target specifically KRAS mutations and can delay or overcome resistance. Immunotherapy has developed rapidly in recent years, and in-depth dissection of the tumor immune microenvironment has led researchers to shift their focus to patients with KRAS mutations, finding that immune factors play an essential role in KRAS-mutant (KRAS-Mut) tumor therapy and targeted drug resistance. Breakthroughs and transitions from targeted therapy to immunotherapy have provided new hope for treating refractory patients. Here, we reviewed KRAS mutation-targeted treatment strategies and resistance issues, focusing on our in-depth exploration of the specific immune status of patients with KRAS mutations and the impact of body immunity following KRAS inhibition. We aimed to guide innovative approaches combining RAS inhibition with immunotherapy, review advances in preclinical and clinical stages, and discuss challenges and future directions.

克氏大鼠肉瘤病毒癌基因同源物(KRAS)是最常发生突变的癌基因,在各种肿瘤类型中都会出现。尽管过去 40 年来人们一直在努力开发针对 KRAS 突变的抑制剂,但最终还是出现了对这些抑制剂的耐药性。要想开发出专门针对 KRAS 突变并能延缓或克服耐药性的新型抑制剂,就必须更准确地了解 KRAS 突变和耐药性产生的机制。近年来,免疫疗法发展迅速,对肿瘤免疫微环境的深入剖析使研究人员将重点转移到KRAS突变患者身上,发现免疫因素在KRAS突变(KRAS-Mut)肿瘤治疗和靶向药物耐药中起着至关重要的作用。从靶向治疗到免疫治疗的突破和转变为治疗难治性患者带来了新的希望。在此,我们回顾了 KRAS 突变靶向治疗策略和耐药性问题,重点深入探讨了 KRAS 突变患者的特殊免疫状态以及 KRAS 抑制后机体免疫的影响。我们旨在指导将 RAS 抑制与免疫疗法相结合的创新方法,回顾临床前和临床阶段的进展,并讨论挑战和未来方向。
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引用次数: 0
Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+ T cell function in esophageal squamous cell carcinoma. 肿瘤衍生的 DEFB1 通过抑制树突状细胞成熟和损害 CD8+ T 细胞功能诱导食管鳞状细胞癌的免疫耐受。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-30 DOI: 10.21147/j.issn.1000-9604.2024.04.01
Jingjing Duan, Haotian Wang, Minglu Liu, Yin Chen, Ning Li, Jieqiong Liu, Lingxiong Wang, Lin Li, Yaru Liu, Pengfei Dong, Xiuxuan Wang, Zhongyi Fan, Shunchang Jiao

Objective: CD8+ T cells are the key effector cells in the anti-tumor immune response. The mechanism underlying the infiltration of CD8+ T cells in esophageal squamous cell carcinoma (ESCC) has not been clearly elucidated.

Methods: Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+ T cells. After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas (TCGA) ESCC data, a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+ T cells. Bioinformatics analyses, histological verification and in vitro experiments were then performed.

Results: DEFB1 was highly expressed in ESCC, and the high expression of DEFB1 was an independent risk factor for overall survival. Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation, migration and apoptosis of ESCC cells, we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics. Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response, and correlate to the infiltration of immature dendritic cell (imDC) in ESCC. Histological analyses further confirmed that there were less CD8+ T cells infiltrated, less CD83+ mature DC (mDC) infiltrated and more CD1a+ imDC infiltrated in those ESCC samples with high expression of DEFB1. After the treatment with recombinant DEFB1 protein, the maturation of DC was hindered significantly, followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.

Conclusions: Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+ T cells, accounting for the immune tolerance in ESCC. The role of DEFB1 in ESCC deserves further exploration.

目的:CD8+ T 细胞是抗肿瘤免疫反应的关键效应细胞:CD8+ T细胞是抗肿瘤免疫反应中的关键效应细胞。食管鳞状细胞癌(ESCC)中 CD8+ T 细胞浸润的机制尚未明确阐明:方法:收集新鲜的 ESCC 组织,并根据 CD8+ T 细胞的浸润密度进行分组。在对这些样本进行转录组测序并与癌症基因组图谱(The Cancer Genome Atlas,TCGA)ESCC数据进行综合分析后,筛选出一种分泌蛋白DEFB1,以探讨其在CD8+ T细胞浸润中的潜在作用。然后进行了生物信息学分析、组织学验证和体外实验:结果:DEFB1在ESCC中高表达,且DEFB1的高表达是总生存率的独立危险因素。由于 DEFB1 的上调或下调并不影响 ESCC 细胞的增殖、迁移和凋亡,我们推测 DEFB1 的致癌作用是通过调节微环境特征实现的。生物信息学分析表明,DEFB1可能在炎症反应和抗肿瘤免疫反应中扮演重要角色,并与ESCC中未成熟树突状细胞(imDC)的浸润相关。组织学分析进一步证实,在DEFB1高表达的ESCC样本中,CD8+ T细胞浸润较少,CD83+成熟树突状细胞(mDC)浸润较少,而CD1a+ imDC浸润较多。用重组DEFB1蛋白处理后,DC的成熟明显受阻,随后T细胞在体外二维和三维培养中的杀伤作用也受到影响:结论:肿瘤来源的DEFB1能抑制DC的成熟并削弱CD8+ T细胞的功能,是ESCC免疫耐受的原因。DEFB1在ESCC中的作用值得进一步探讨。
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引用次数: 0
CSCO guidelines for colorectal cancer version 2024: Updates and discussions. 结直肠癌 CSCO 指南 2024 版:更新和讨论。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-06-30 DOI: 10.21147/j.issn.1000-9604.2024.03.01
Liubo Chen, Hanguang Hu, Ying Yuan, Shanshan Weng
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引用次数: 0
Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer. HER2阳性胃癌对曲妥珠单抗耐药的机制。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-06-30 DOI: 10.21147/j.issn.1000-9604.2024.03.07
Zhifei Li, Huan Zhao, Huihui Hu, Haili Shang, Yongjing Ren, Wenhui Qiu, Hao Su, Huifang Lyu, Xiaobing Chen

Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.

胃癌是全球发病率最高的癌症之一,人表皮生长因子受体 2(HER2)阳性病例约占总病例的 20%。目前,曲妥珠单抗+化疗是HER2阳性晚期胃癌患者的推荐一线治疗方案,这种联合疗法在HER2靶向治疗中表现出了确切的疗效。然而,治疗过程中耐药性的出现大大降低了治疗效果;因此,研究耐药性的潜在机制势在必行。在本综述文章中,我们全面介绍了HER2阳性胃癌病例对曲妥珠单抗耐药的多种机制,旨在为纠正曲妥珠单抗耐药相关问题和制定后续治疗策略提供启示。
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引用次数: 0
Unraveling links between aging, circadian rhythm and cancer: Insights from evidence-based analysis. 揭示衰老、昼夜节律与癌症之间的联系:循证分析的启示。
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-06-30 DOI: 10.21147/j.issn.1000-9604.2024.03.09
Dechao Feng, Yuhan Xiao, Jie Wang, Ruicheng Wu, Zhouting Tuo, Koo Han Yoo, Wuran Wei, Dilinaer Wusiman, Zhipeng Wang, Dengxiong Li, Yubo Yang, William C Cho, Mang Ke

Aging and circadian rhythms have been connected for decades, but their molecular interaction has remained unknown, especially for cancers. In this situation, we summarized the current research actuality and problems in this field using the bibliometric analysis. Publications in the PubMed and Web of Science databases were retrieved. Overall, there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer. Researchers from USA, Germany, Italy, China and England have greater studies than others. Top three publication institutions are University of California System, UDICE-French Research Universities and University of Texas System. Current research hotspots include oxidative stress, breast cancer, melatonin, cell cycle, calorie restriction, prostate cancer and NF-KB. In conclusion, results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer. These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

衰老与昼夜节律之间的联系已有几十年的历史,但它们之间的分子相互作用却一直不为人知,尤其是在癌症方面。在这种情况下,我们通过文献计量分析总结了该领域目前的研究现状和问题。我们检索了 PubMed 和 Web of Science 数据库中的文献。总体而言,癌症领域有关衰老和昼夜节律的论文数量呈上升趋势。来自美国、德国、意大利、中国和英国的研究人员的研究成果较多。发表论文最多的三个机构分别是加利福尼亚大学系统、法国研究型大学联盟(UDICE-French Research Universities)和德克萨斯大学系统。目前的研究热点包括氧化应激、乳腺癌、褪黑激素、细胞周期、卡路里限制、前列腺癌和 NF-KB。总之,文献计量分析的结果表明,许多方法都涉及癌症中衰老与昼夜节律之间复杂的相互作用。这些既有的和新兴的研究方向为我们探索癌症中衰老和昼夜节律的调控机制提供了指导,也为开发新的研究途径提供了参考。
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引用次数: 0
Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis. 同源重组缺陷阳性非小细胞肺癌在中国人群中的临床和分子意义:基因组和转录的综合分析
IF 7 2区 医学 Q1 ONCOLOGY Pub Date : 2024-06-30 DOI: 10.21147/j.issn.1000-9604.2024.03.05
Yifei Wang, Yidan Ma, Lei He, Jun Du, Xiaoguang Li, Peng Jiao, Xiaonan Wu, Xiaomao Xu, Wei Zhou, Li Yang, Jing Di, Changbin Zhu, Liming Xu, Tianlin Sun, Lin Li, Dongge Liu, Zheng Wang

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care.

Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed.

Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens.

Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

目的:同源重组缺陷(HRD)在乳腺癌、卵巢癌和前列腺癌中的临床意义已经确立,但HRD在非小细胞肺癌(NSCLC)中的价值尚未得到充分研究。本研究旨在系统分析未经治疗的 NSCLC 的 HRD 状态及其与患者预后的关系,以进一步指导临床治疗:方法:共回顾性纳入了355例未经治疗的NSCLC患者。HRD状态使用AmoyDx基因组疤痕评分(GSS)进行评估,评分≥50分为HRD阳性。分析了HRD阳性和HRD阴性患者的基因组、转录组、肿瘤微环境特征和预后:结果:HRD阳性患者占25.1%(89/355)。与HRD阴性患者相比,HRD阳性患者有更多的体细胞致病性同源重组修复(HRR)突变,肿瘤突变负荷(TMB)更高(表皮生长因子受体(EGFR)/无性淋巴瘤激酶(ALK)突变NSCLC中的PMET和MYC,以及EGFR/ALK野生型NSCLC中更多的PIK3CA和AURKA)。HRD阳性的NSCLC显示出更高的肿瘤增殖和免疫抑制活性。HRD阴性NSCLC显示出主要组织相容性复合体(MHC)-II、干扰素(IFN)-γ和效应记忆CD8+ T细胞的活化特征。HRD阳性患者的预后较差,接受靶向治疗(第一代和第三代表皮生长因子受体抑制剂-TKIs)后的无进展生存期(PFS)较短(P=0.042)。此外,HRD阳性、表皮生长因子受体/ALK野生型患者对无铂免疫治疗方案的反应较低:结论:在HRD阳性NSCLC中发现了独特的基因组和转录特征。HRD阳性NSCLC预后差,对表皮生长因子受体抑制剂(EGFR-TKIs)和免疫疗法反应差。这项研究强调了HRD阳性NSCLC中潜在的可操作改变,为这些患者提出了可能的联合治疗策略。
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Chinese Journal of Cancer Research
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