液体活检已经成为了癌症检测的一大热门词汇，许多液体活检都是通过循环肿瘤DNA（ctDNA）进行检测，ctDNA就是肿瘤细胞遗传物质脱落后进入血液的碎片。

来自剑桥大学的科学家们建立了一种新方法，通过分析ctDNA的大小，在血液中检测难以追踪的肿瘤DNA（又称ctDNA），这种方法可提高对罹患脑癌、肾癌、胰腺癌患者ctDNA的检测能力。

这一研究成果公布在11月7日的Science Translational Medicine杂志上，由剑桥大学英国剑桥癌症研究所的Nitzan Rosenfeld博士领导完成。同期Science Translational Medicine杂志配发了评论性文章。

ctDNA这种活检方式比其他的癌症检测方法具有潜在的优势，因为首先它是微创的，可以在治疗期间随时进行，从而医生可以实时监测肿瘤的分子变化。而且这不会因为成像的不确定性而发生误判，最后ctDNA也可能代表了患者整体的肿瘤状况，而不仅仅是局限于受检测部分的肿瘤。

但是，ctDNA难以确认，因为它通常在数量上远远少于更大数量的也在血液中循环的非癌DNA。以往的研究已经证明，血液循环中来自胎儿的DNA片段因为较短而能与母亲的DNA区分开来，这一发现帮助提高了产前诊断的敏感性。

在这篇文章中，研究人员设计了一种新的方法，考虑的是ctDNA的大小、片段差异，而不是ctDNA的基因组改变。他们利用全基因组测序来检查来自200名癌症患者的344个血浆样本中的ctDNA片段的大小。

结果发现了与每个患者癌症类型相关的ctDNA生物学特征，研发了用于选择特定ctDNA片段大小的计算方法。研究人员发现，长度在90-150碱基对之间的ctDNA片段可提高对罹患脑癌、肾癌、胰腺癌患者ctDNA的检测能力。

Rosenfeld博士指出，这种通过对ctDNA大小的选择将会对检测体液中其它类型的DNA产生影响。（来源：生物通）

Enhanced detection of circulating tumor DNA by fragment size analysis

Abstract  Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.

原文链接：http://stm.sciencemag.org/content/scitransmed/10/466/eaat4921.full.pdf