Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer.
Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer.
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DOI：
10.1016/j.ebiom.2016.06.032
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发表时间：
2016-08
期刊：
影响因子：
11.1
通讯作者：
Brennan P
中科院分区：
文献类型：
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作者：
Fernandez-Cuesta L;Perdomo S;Avogbe PH;Leblay N;Delhomme TM;Gaborieau V;Abedi-Ardekani B;Chanudet E;Olivier M;Zaridze D;Mukeria A;Vilensky M;Holcatova I;Polesel J;Simonato L;Canova C;Lagiou P;Brambilla C;Brambilla E;Byrnes G;Scelo G;Le Calvez-Kelm F;Foll M;McKay JD;Brennan P
循环肿瘤DNA（ctDNA）正在成为诊断后监测的关键潜在生物标志物，但它也可能在临床前癌症的检测中发挥关键作用。小细胞肺癌（SCLC）是早期检测的一个很好的候选者，因为晚期疾病没有成功的治疗选择，并且它几乎显示出TP53的普遍失活。我们评估了从51例SCLC病例和123例非癌症对照的血浆中提取的无细胞DNA（cfDNA）中TP53突变的存在。我们使用专门设计的管道识别突变，以准确检测非常低分数的变体。我们在49%的SCLC患者和11.4%的非癌症对照的cfDNA中检测到TP53突变。当按阶段对51例初始SCLC病例进行分层时，在35.7%的早期SCLC患者和54.1%的晚期SCLC患者的cfDNA中检测到TP53突变。对照组的结果在102名非癌症对照的独立系列中进一步重复了10.8%。在225个非癌症对照中的11%中检测到TP53突变表明，在没有任何癌症诊断的个体中cfDNA的体细胞突变是常见的，并且对ctDNA筛查测试的开发构成了严峻的挑战。CtDNA可能在临床前癌症的检测中发挥关键作用。在具有早期肿瘤的SCLC患者的cfDNA中可检测到TP53突变。在非癌症对照中检测TP53突变对ctDNA筛查测试的发展提出了严峻的挑战。无细胞DNA（cfDNA）具有监测治疗反应和复发的潜力，也可用于早期检测。这是第一项报告在诊断为小细胞肺癌（SCLC）的病例中检测循环肿瘤DNA（ctDNA）的研究。我们的结果表明，TP53突变在SCLC患者的cfDNA中是可检测的，包括那些具有早期肿瘤的患者。重要的是，我们还提供了癌症样TP53突变存在于非癌症对照中的证据，这对ctDNA筛查测试的发展构成了严峻的挑战。
Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests. CtDNA may play a crucial role in the detection of pre-clinical cancer. TP53 mutations are detectable in the cfDNA of SCLC patients with early-stage tumors. Detection of TP53 mutations in non-cancer controls poses serious challenges for the development of ctDNA screening tests. Cell-free DNA (cfDNA) has potential for monitoring response to treatment and relapse, but also for early detection. This is the first study reporting the detection of circulating-tumor DNA (ctDNA) in cases diagnosed with small-cell lung cancer (SCLC). Our results show that TP53 mutations are detectable in the cfDNA of SCLC patients including those with early-stage tumors. Importantly, we also provide evidence that cancer-like TP53 mutations are present in non-cancer controls, which poses serious challenges for the development of ctDNA screening tests.