Department of Plastic and Hand Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Plastic and Reconstructive Surgery, Sir Charles Gairdner Hospital, Perth, WA, Australia.
Int J Cancer. 2019 Aug 15;145(4):1148-1161. doi: 10.1002/ijc.32216. Epub 2019 Mar 9.
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin. About 50% of patients with STS experience relapse and more than 30% will die within 10 years after diagnosis. In this study we investigated circulating free DNA (cfDNA) and tumor-specific genetic alterations therein (circulating tumor DNA, ctDNA) as diagnostic biomarkers. Plasma concentrations and fragmentation of cfDNA was analyzed with quantitative PCR. Patients with STS (n = 64) had significantly higher plasma concentrations and increased fragmentation of cfDNA when compared to patients in complete remission (n = 19) and healthy controls (n = 41) (p < 0.01 and p < 0.001). Due to overlapping values between patients with STS and controls, the sensitivity and specificity of these assays is limited. Sensitive assays to detect genomic alterations in cfDNA of synovial sarcomas (t(X;18)), myxoid liposarcomas (t(12;16) and TERT C228T promoter mutation) and well-differentiated/de-differentiated liposarcomas (MDM2 amplifications) were established. ctDNA was quantified in nine liposarcoma patients during the course of their treatment. Levels of breakpoint t(12;16) and TERT C228T ctDNA correlated with the clinical course and tumor burden in patients with myxoid liposarcomas (n = 4). ctDNA could detect minimal residual disease and tumor recurrence. In contrast, detection of MDM2 amplifications was not sensitive enough to detect tumors in patients with well-differentiated/de-differentiated liposarcomas (n = 5). Genotyping of cfDNA for tumor specific genetic alterations is a feasible and promising approach for monitoring tumor activity in patients with myxoid liposarcomas. Detection of ctDNA during follow-up examinations despite negative standard imaging studies might warrant more sensitive imaging (e.g. PET-CT) or closer follow-up intervals to timely localize and treat recurrences.
软组织肉瘤（STS）是一种罕见的间充质来源的肿瘤。大约 50%的 STS 患者会复发，超过 30%的患者在诊断后 10 年内死亡。在这项研究中，我们研究了循环游离 DNA（cfDNA）及其内的肿瘤特异性遗传改变（循环肿瘤 DNA，ctDNA）作为诊断生物标志物。使用定量 PCR 分析 cfDNA 的血浆浓度和片段化。与完全缓解的患者（n=19）和健康对照者（n=41）相比，STS 患者（n=64）的血浆 cfDNA 浓度显著升高，片段化程度增加（p<0.01 和 p<0.001）。由于 STS 患者和对照组之间存在重叠值，因此这些检测的敏感性和特异性有限。建立了用于检测滑膜肉瘤（t(X;18)）、黏液样脂肪肉瘤（t(12;16)和 TERT C228T 启动子突变）和去分化/未分化脂肪肉瘤（MDM2 扩增）cfDNA 中基因组改变的敏感检测方法。在 9 名脂肪肉瘤患者的治疗过程中定量检测了 ctDNA。黏液样脂肪肉瘤患者（n=4）的断裂点 t(12;16)和 TERT C228T ctDNA 水平与临床过程和肿瘤负荷相关。ctDNA 可检测到微小残留疾病和肿瘤复发。相比之下，检测 MDM2 扩增不足以检测去分化/未分化脂肪肉瘤患者的肿瘤（n=5）。cfDNA 肿瘤特异性遗传改变的基因分型是监测黏液样脂肪肉瘤患者肿瘤活性的一种可行且有前途的方法。尽管标准影像学研究为阴性，但在随访检查中检测到 ctDNA 可能需要更敏感的影像学（例如 PET-CT）或更密切的随访间隔，以及时定位和治疗复发。
