Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients
Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients
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DOI：
10.1073/pnas.1500076112
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发表时间：
2015-03-17
影响因子：
11.1
通讯作者：
Lo, Y. M. Dennis
中科院分区：
文献类型：
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作者：
Jiang, Peiyong;Chan, Carol W. M.;Lo, Y. M. Dennis
对肿瘤来源的循环无细胞DNA的分析为进行液体活检以评估实体肿瘤开辟了新的可能性。尽管它的临床潜力已经被越来越多地认识到，但肿瘤来源的无细胞DNA的许多方面的生物学特性仍然不清楚。关于这种血浆DNA分子的大小分布，一些研究报告发现肿瘤来源的血浆DNA的完整性增加，而另一些研究发现证据表明，肿瘤释放的血浆DNA分子可能更短。在这里，我们对90名肝细胞癌患者、67名慢性乙肝患者、36名乙肝相关性肝硬变患者和32名健康对照的血浆DNA大小分布进行了详细的分析。我们使用大规模并行测序实现了以单碱基分辨率和全基因组方式测量血浆DNA大小。利用染色体臂水平z分数分析(CAZA)进一步鉴定了肿瘤来源的血浆DNA分子，这有助于研究其特定的大小分布。我们发现在肝细胞癌患者的血浆中存在异常的短和长DNA分子群体。短拷贝优先携带与肿瘤相关的拷贝数异常。我们进一步发现，肝细胞癌患者血浆中的线粒体DNA含量升高。这些分子比血浆中的核DNA短得多。这些结果提高了我们对肿瘤来源的循环无细胞DNA的大小分布的理解，并可能进一步增强我们将血浆DNA用作分子诊断工具的能力。
The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.