A feasibility study of colorectal cancer diagnosis via circulating tumor DNA derived CNV detection

Circulating tumor DNA (ctDNA) has shown great promise as a biomarker for early detection of cancer. However, due to the low abundance of ctDNA, especially at early stages, it is hard to detect at high accuracies while keeping sequencing costs low. Here we present a pilot stage study to detect large scale somatic copy numbers variations (CNVs), which contribute more molecules to ctDNA signal compared to point mutations, via cell free DNA sequencing. We show that it is possible to detect somatic CNVs in early stage colorectal cancer (CRC) patients and subsequently discriminate them from normal patients. With 25 normal and 24 CRC samples, we achieve 100% specificity (lower bound confidence interval: 86%) and ~79% sensitivity (95% confidence interval: 63% - 95%,), though the performance should be considered with caution given the limited sample size. We report a lack of concordance between the CNVs detected via cfDNA sequencing and CNVs identified in parent tissue samples. However, recent findings suggest that a lack of concordance is expected for CNVs in CRC because of their sub-clonal nature. Finally, the CNVs we detect very likely contribute to cancer progression as they lie in functionally important regions, and have been shown to be associated with CRC specifically. This study paves the path for a larger scale exploration of the potential of CNV detection for both diagnoses and prognoses of cancer.

循环肿瘤DNA（ctDNA）在癌症的早期检测中展现出巨大的潜力，作为生物标志物。然而，鉴于ctDNA在早期阶段含量稀少，要实现高准确率的同时降低测序成本，检测任务颇具挑战。本研究旨在通过游离DNA测序技术，对大规模体细胞拷贝数变异（CNVs）进行试点研究，这些变异相较于点突变，为ctDNA信号提供了更多的分子贡献。研究结果表明，在早期结直肠癌（CRC）患者中检测体细胞CNVs并区分其与正常患者成为可能。在25例正常样本和24例CRC样本中，我们实现了100%的特异性（置信区间下限：86%）以及约79%的敏感性（95%置信区间：63% - 95%），但鉴于样本量有限，这一性能应谨慎评估。我们观察到，通过cfDNA测序检测到的CNVs与来自原组织样本中识别的CNVs之间缺乏一致性。然而，近期的研究发现，由于CRC中CNVs的亚克隆特性，这种不一致性是预期的。最终，我们检测到的CNVs很可能位于功能重要区域，并且已证实与CRC特异性相关，它们很可能对癌症的进展起到促进作用。本研究为更大规模的探索CNV检测在癌症诊断和预后方面的潜力铺平了道路。