PDF(Pubmed)
Abstract：
UNASSIGNED: Current surveillance modalities of osteosarcoma relapse exhibit limited sensitivity and specificity. Although circulating tumor DNA (ctDNA) has been established as a biomarker of minimal residual disease (MRD) in many solid tumors, a sensitive ctDNA detection technique has not been thoroughly explored for longitudinal MRD detection in osteosarcoma.
UNASSIGNED: From August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors.
UNASSIGNED: WES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up.
UNASSIGNED: Our study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management.
UNASSIGNED: The Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010).
UNASSIGNED: From August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors.
UNASSIGNED: WES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up.
UNASSIGNED: Our study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management.
UNASSIGNED: The Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010).
摘要：
■目前骨肉瘤复发的监测模式显示出有限的敏感性和特异性。尽管循环肿瘤DNA（ctDNA）已被确定为许多实体瘤中微小残留病（MRD）的生物标志物，对于骨肉瘤的纵向MRD检测，尚未彻底探索灵敏的ctDNA检测技术。
■自2019年8月至2023年6月，对中山大学附属第一医院诊断为骨肉瘤的59例患者进行了评估。通过肿瘤组织的全外显子组测序(WES)开发肿瘤信息MRD组。在治疗期间收集纵向血液样品并进行基于多重PCR的下一代测序(NGS)。卡普兰-迈耶曲线和对数秩检验用于比较结果，并进行Cox回归分析以确定预后因素.
■对83例患者的WES分析显示出实质性的突变异质性，非复发突变基因占58.1%。85.5%(71/83)的患者成功获得了肿瘤信息MRD组。在59名成功定制MRD面板和可用血液样本的患者中，13例患者术后ctDNA检测呈阳性。与ctDNA阳性的患者相比，术后ctDNA阴性的患者具有更好的无事件生存率（EFS）。手术后1-6个月，辅助化疗后，术后6个月以上(p<0.05)。在单变量和多变量Cox回归分析中，ctDNA结果是EFS的显著预测因子(p<0.05)。ctDNA检测先于5例阳性显像，平均提前期为92.6天。三十九名病人仍然无病,在随访期间，ctDNA结果始终为阴性或转为阴性。
■我们的研究强调了肿瘤信息深度测序ctDNA在骨肉瘤MRD监测中的适用性，根据我们的知识，表示迄今为止最大的队列。ctDNA检测是一个重要的预后因素，与标准成像相比，能够早期识别肿瘤复发和进展，从而为指导骨肉瘤患者管理提供有价值的见解。
■国家自然科学基金资助（编号：82072964,82072965,82203798,82203026),广东省自然科学基金(编号：2023A1515012659,2023A1515010302),和广东省基础与应用基础研究基金区域组合项目（编号：2020A1515110010）。
■自2019年8月至2023年6月，对中山大学附属第一医院诊断为骨肉瘤的59例患者进行了评估。通过肿瘤组织的全外显子组测序(WES)开发肿瘤信息MRD组。在治疗期间收集纵向血液样品并进行基于多重PCR的下一代测序(NGS)。卡普兰-迈耶曲线和对数秩检验用于比较结果，并进行Cox回归分析以确定预后因素.
■对83例患者的WES分析显示出实质性的突变异质性，非复发突变基因占58.1%。85.5%(71/83)的患者成功获得了肿瘤信息MRD组。在59名成功定制MRD面板和可用血液样本的患者中，13例患者术后ctDNA检测呈阳性。与ctDNA阳性的患者相比，术后ctDNA阴性的患者具有更好的无事件生存率（EFS）。手术后1-6个月，辅助化疗后，术后6个月以上(p<0.05)。在单变量和多变量Cox回归分析中，ctDNA结果是EFS的显著预测因子(p<0.05)。ctDNA检测先于5例阳性显像，平均提前期为92.6天。三十九名病人仍然无病,在随访期间，ctDNA结果始终为阴性或转为阴性。
■我们的研究强调了肿瘤信息深度测序ctDNA在骨肉瘤MRD监测中的适用性，根据我们的知识，表示迄今为止最大的队列。ctDNA检测是一个重要的预后因素，与标准成像相比，能够早期识别肿瘤复发和进展，从而为指导骨肉瘤患者管理提供有价值的见解。
■国家自然科学基金资助（编号：82072964,82072965,82203798,82203026),广东省自然科学基金(编号：2023A1515012659,2023A1515010302),和广东省基础与应用基础研究基金区域组合项目（编号：2020A1515110010）。
