Exact Sciences Corporation, Madison, Wisconsin.
Clin Gastroenterol Hepatol. 2013 Oct;11(10):1313-8. doi: 10.1016/j.cgh.2013.04.023. Epub 2013 Apr 29.
BACKGROUND & AIMS: Colorectal cancer (CRC) and advanced precancers can be detected noninvasively by analyses of exfoliated DNA markers and hemoglobin in stool. Practical and cost-effective application of a stool DNA-based (sDNA) test for general CRC screening requires high levels of accuracy and high-capacity throughput. We optimized an automated sDNA assay and evaluated its clinical performance.
In a blinded, multicenter, case-control study, we collected stools from 459 asymptomatic patients before screening or surveillance colonoscopies and from 544 referred patients. Cases included CRC (n = 93), advanced adenoma (AA) (n = 84), or sessile serrated adenoma ≥1 cm (SSA) (n = 30); controls included nonadvanced polyps (n = 155) or no colonic lesions (n = 641). Samples were analyzed by using an automated multi-target sDNA assay to measure β-actin (a marker of total human DNA), mutant KRAS, aberrantly methylated BMP3 and NDRG4, and fecal hemoglobin. Data were analyzed by a logistic algorithm to categorize patients as positive or negative for advanced colorectal neoplasia (CRC, advanced adenoma, and/or SSA ≥1 cm).
At 90% specificity, sDNA analysis identified individuals with CRC with 98% sensitivity. Its sensitivity for stage I cancer was 95%, for stage II cancer it was 100%, for stage III cancer it was 96%, for stage IV cancer it was 100%, and for stages I-III cancers it was 97% (nonsignificant P value). Its sensitivity for advanced precancers (AA and SSA) ≥1 cm was 57%, for >2 cm it was 73%, and for >3 cm it was 83%. The assay detected AA with high-grade dysplasia with 83% sensitivity.
We developed an automated, multi-target sDNA assay that detects CRC and premalignant lesions with levels of accuracy previously demonstrated with a manual process. This automated high-throughput system could be a widely accessible noninvasive approach to general CRC screening.
通过分析粪便中脱落的 DNA 标志物和血红蛋白，非侵入性地检测结直肠癌（CRC）和高级癌前病变。为使基于粪便 DNA（sDNA）的测试实用且具有成本效益，广泛应用于一般 CRC 筛查，需要高准确度和高通量。我们优化了一种自动化 sDNA 检测方法，并评估了其临床性能。
在一项盲法、多中心病例对照研究中，我们在筛查或监测结肠镜检查前收集了 459 例无症状患者的粪便，还收集了 544 例转诊患者的粪便。病例包括 CRC（n=93）、高级腺瘤（AA）（n=84）或≥1cm 的无蒂锯齿状腺瘤（SSA）（n=30）；对照组包括非高级息肉（n=155）或无结肠病变（n=641）。采用自动化多靶 sDNA 检测方法分析样本，以测量 β-肌动蛋白（总人 DNA 的标志物）、突变 KRAS、异常甲基化的 BMP3 和 NDRG4 以及粪便血红蛋白。使用逻辑算法分析数据，将患者归类为高级结直肠肿瘤（CRC、高级腺瘤和/或≥1cm 的 SSA）阳性或阴性。
在 90%特异性时，sDNA 分析对 CRC 的敏感度为 98%。其对 I 期癌症的敏感度为 95%，对 II 期癌症为 100%，对 III 期癌症为 96%，对 IV 期癌症为 100%，对 I-III 期癌症为 97%（无显著统计学意义）。其对高级癌前病变（AA 和 SSA）≥1cm 的敏感度为 57%，对>2cm 的敏感度为 73%，对>3cm 的敏感度为 83%。该检测方法对高级别异型增生的 AA 具有 83%的敏感度。
我们开发了一种自动化、多靶 sDNA 检测方法，其检测 CRC 和癌前病变的准确度与之前使用手工过程所达到的准确度相当。这种自动化高通量系统可能成为一种广泛可及的非侵入性通用 CRC 筛查方法。
