Wrangle John, Machida Emi Ota, Danilova Ludmila, Hulbert Alicia, Franco Noreli, Zhang Wei, Glöckner Sabine C, Tessema Mathewos, Van Neste Leander, Easwaran Hariharan, Schuebel Kornel E, Licchesi Julien, Hooker Craig M, Ahuja Nita, Amano Jun, Belinsky Steven A, Baylin Stephen B, Herman James G, Brock Malcolm V
Authors' Affiliations: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland; Department of Molecular Biotechnology, Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium; MDxHealth Inc, Irvine, California; Shinshu University School of Medicine, Asahi, Matsumoto, Nagano, Japan; and Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
Clin Cancer Res. 2014 Apr 1;20(7):1856-64. doi: 10.1158/1078-0432.CCR-13-2109. Epub 2014 Jan 31.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer.
Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples.
We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort.
This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC.
非小细胞肺癌（NSCLC）是全球癌症死亡的主要原因。新型诊断生物标志物可能会增强现有的NSCLC筛查方法以及手术标本的分子诊断测试，从而更准确地对辅助化疗的候选者进行分层和分期。CpG岛的高甲基化是从正常组织转变为癌症过程中常见且重要的改变。
按照先前验证的用于发现癌症特异性高甲基化变化的方法，我们用去甲基化剂地西他滨或曲古抑菌素A处理了8种NSCLC细胞系。我们使用一个大型公开可用数据库和两个独立的原发性样本队列对研究结果进行了验证。
我们鉴定出了300多个候选基因。利用癌症基因组图谱（TCGA）并进行广泛筛选以优化我们的候选基因，使其具有最大的区分肿瘤与正常组织的能力，我们定义了一个三基因组合，即CDO1、HOXA9和TAC1，随后我们在两个独立的原发性NSCLC样本队列中对其进行了验证。这个三基因组合具有100%的特异性，在75个TCGA正常样本和7个原发性正常样本中均未显示甲基化，并且根据队列不同，对NSCLC的敏感性为83%至99%。
这种敏感性和特异性程度对于诊断NSCLC的最早阶段可能具有很高的价值。将这个三基因组合添加到其他先前验证的甲基化生物标志物中，在NSCLC的早期诊断和分子分期方面都具有巨大的前景。
