Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
Clin Cancer Res. 2023 Jun 1;29(11):2085-2094. doi: 10.1158/1078-0432.CCR-22-2912.
Cell-free DNA (cfDNA) analysis is a powerful tool for noninvasively predicting patient outcomes. We analyzed the size distribution of cfDNA and assessed its prognostic and diagnostic values in an osteosarcoma cohort.
The fragment size distribution and level of cfDNA were analyzed in 15 healthy donors and 50 patients with osteosarcoma using automated capillary electrophoresis. The prognostic performance of cfDNA size analysis was assessed using univariate and multivariable analyses. By performing whole-genome sequencing of matched cfDNA and osteosarcoma tissue samples, we investigated the correlation between the size and mutation profiles of cfDNA and the mutation concordance between cfDNA and paired tissue tumors.
The size of cfDNA fragments in patients with osteosarcoma was significantly shorter than in healthy donors, with the integrative analysis of size distribution and level of cfDNA achieving a high specificity and sensitivity of 100%. The short cfDNA fragment (150-bp cut-off) was an independent prognostic predictor in this osteosarcoma cohort [HR, 9.03; 95% confidence interval (CI), 1.13-72.20; P = 0.038]. Shortened cfDNA fragments were found to be a major source of mutations. Enrichment of cfDNA fragments with less than or equal to 150 bp by in silico size selection remarkedly improved the detection of copy-number variation signals up to 2.3-fold when compared with total cfDNA, with a higher concordance rate with matched osteosarcoma tissue.
This finding demonstrated the potential of cfDNA size profiling in the stratification of poor prognostic patients with osteosarcoma. The short fragments of cfDNA are a promising source for boosting the detection of significant mutations in osteosarcoma. See related commentary by Weiser et al., p. 2017.
无细胞 DNA（cfDNA）分析是一种非侵入性预测患者预后的有力工具。我们分析了 cfDNA 的大小分布，并在骨肉瘤队列中评估了其预后和诊断价值。
使用自动化毛细管电泳分析了 15 名健康供体和 50 名骨肉瘤患者的 cfDNA 片段大小分布和水平。通过单变量和多变量分析评估了 cfDNA 大小分析的预后性能。通过对匹配的 cfDNA 和骨肉瘤组织样本进行全基因组测序，我们研究了 cfDNA 大小和突变谱与 cfDNA 和配对组织肿瘤之间的突变一致性之间的相关性。
骨肉瘤患者的 cfDNA 片段大小明显短于健康供体，大小分布和水平的综合分析特异性和灵敏度均达到 100%。在这个骨肉瘤队列中，短 cfDNA 片段（150-bp 截断值）是一个独立的预后预测因子[HR，9.03；95%置信区间（CI），1.13-72.20；P=0.038]。较短的 cfDNA 片段是突变的主要来源。通过计算机大小选择富集小于或等于 150 bp 的 cfDNA 片段，与总 cfDNA 相比，显著提高了 2.3 倍的拷贝数变异信号检测，与匹配的骨肉瘤组织的一致性率更高。
这一发现表明 cfDNA 大小分析在骨肉瘤患者预后不良的分层中具有潜力。cfDNA 的短片段是提高骨肉瘤中显著突变检测的有前途的来源。请参阅 Weiser 等人的相关评论，第 2017 页。
