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Integrating genomic features for non-invasive early lung cancer detection
Nature ( IF 64.8 ) Pub Date : 2020-03-25 , DOI: 10.1038/s41586-020-2140-0
Jacob J Chabon 1, 2 , Emily G Hamilton 3 , David M Kurtz 4, 5, 6 , Mohammad S Esfahani 1, 4 , Everett J Moding 1, 7 , Henning Stehr 8 , Joseph Schroers-Martin 4, 5 , Barzin Y Nabet 1, 7 , Binbin Chen 4, 9 , Aadel A Chaudhuri 10, 11, 12 , Chih Long Liu 4 , Angela B Hui 1, 7 , Michael C Jin 4 , Tej D Azad 4 , Diego Almanza 3 , Young-Jun Jeon 1 , Monica C Nesselbush 3 , Lyron Co Ting Keh 1 , Rene F Bonilla 7 , Christopher H Yoo 7 , Ryan B Ko 7 , Emily L Chen 7 , David J Merriott 7 , Pierre P Massion 13, 14 , Aaron S Mansfield 15 , Jin Jen 16 , Hong Z Ren 16 , Steven H Lin 17 , Christina L Costantino 18, 19 , Risa Burr 18, 20 , Robert Tibshirani 21, 22 , Sanjiv S Gambhir 6, 23 , Gerald J Berry 8 , Kristin C Jensen 8, 24 , Robert B West 8 , Joel W Neal 4 , Heather A Wakelee 4 , Billy W Loo 7 , Christian A Kunder 8 , Ann N Leung 23 , Natalie S Lui 25 , Mark F Berry 25 , Joseph B Shrager 24, 25 , Viswam S Nair 23, 26, 27 , Daniel A Haber 18, 20, 28 , Lecia V Sequist 18, 28 , Ash A Alizadeh 1, 2, 4, 5 , Maximilian Diehn 1, 2, 7
Affiliation  

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed ‘lung cancer likelihood in plasma’ (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.



中文翻译:

整合基因组特征用于非侵入性早期肺癌检测

对高危成人进行放射检查可降低肺癌相关死亡率1,2;然而,少数符合条件的个人在美国接受了此类筛查3,4。基于血液的测试的可用性可以增加筛查的吸收。在这里,我们介绍了通过深度测序 (CAPP-Seq) 5对癌症个性化分析的改进,一种用于分析循环肿瘤 DNA (ctDNA) 的方法,以更好地促进筛查应用。我们表明,尽管早期肺癌中的水平非常低,但大多数患者在治疗前都存在 ctDNA,并且它的存在具有很强的预后意义。我们还发现,肺癌患者和风险匹配对照者的游离 DNA (cfDNA) 中的大多数体细胞突变反映了克隆性造血功能,并且是非复发性的。与肿瘤衍生的突变相比,克隆性造血突变发生在较长的 cfDNA 片段上,并且缺乏与吸烟相关的突变特征。将这些发现与其他分子特征相结合,我们开发并前瞻性地验证了一种称为“血浆中肺癌可能性”(Lung-CLiP)的机器学习方法,这可以有力地将早期肺癌患者与风险匹配的对照区分开来。这种方法实现了与肿瘤知情 ctDNA 检测相似的性能,并能够调整检测特异性以促进不同的临床应用。我们的研究结果确立了 cfDNA 在肺癌筛查中的潜力,并强调了风险匹配病例和对照在基于 cfDNA 的筛查研究中的重要性。

更新日期:2020-03-25
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