Department of Oncology, Johns Hopkins University, Baltimore, MD, USA.
Research Institute, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, South Korea.
Clin Cancer Res. 2013 Dec 1;19(23):6544-6555. doi: 10.1158/1078-0432.CCR-12-3224. Epub 2013 Oct 2.
Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here, we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer.
We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of eight promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis, including methylation and expression. We used a nanoparticle-enabled methylation on beads (MOB) technology to detect early-stage pancreatic cancers by analyzing DNA methylation in patient serum.
We identified two novel genes, BNC1 (92%) and ADAMTS1 (68%), that showed a high frequency of methylation in pancreatic cancers (n = 143), up to 100% in PanIN-3 and 97% in stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n = 42) from patients with pancreatic cancer, with a sensitivity for BNC1 of 79% [95% confidence interval (CI), 66%-91%] and for ADAMTS1 of 48% (95% CI, 33%-63%), whereas specificity was 89% for BNC1 (95% CI, 76%-100%) and 92% for ADAMTS1 (95% CI, 82%-100%). Overall sensitivity using both markers is 81% (95% CI, 69%-93%) and specificity is 85% (95% CI, 71%-99%).
Promoter DNA methylation of BNC1 and ADAMTS1 is a potential biomarker to detect early-stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early detection of pancreatic cancer and has the potential to improve mortality from this disease.
胰腺癌是癌症死亡的第四大主要原因，目前尚无可靠的方法可用于早期检测这种疾病。在这里，我们确定了 BNC1 和 ADAMTS1 的癌症特异性启动子 DNA 甲基化为一种很有前途的生物标志物检测策略，值得在胰腺癌中进行研究。
我们使用全基因组药物转录组方法来鉴定胰腺癌细胞系中新颖的癌症特异性 DNA 甲基化改变。在八个有前途的基因中，我们将研究重点放在 BNC1 和 ADAMTS1 上，以进行进一步的下游分析，包括甲基化和表达。我们使用纳米颗粒增强的珠子上甲基化（MOB）技术，通过分析患者血清中的 DNA 甲基化来检测早期胰腺癌。
我们鉴定了两个新基因，BNC1（92%）和 ADAMTS1（68%），它们在胰腺癌（n=143）中具有高甲基化频率，在 PanIN-3 中高达 100%，在 I 期浸润性癌症中高达 97%。使用纳米颗粒增强的 MOB 技术，可以在来自胰腺癌患者的血清样本（n=42）中检测到这些改变，BNC1 的灵敏度为 79%（95%CI，66%-91%），ADAMTS1 的灵敏度为 48%（95%CI，33%-63%），而特异性分别为 89%（95%CI，76%-100%）和 92%（95%CI，82%-100%）。使用这两个标志物的总体灵敏度为 81%（95%CI，69%-93%），特异性为 85%（95%CI，71%-99%）。
BNC1 和 ADAMTS1 的启动子 DNA 甲基化是检测早期胰腺癌的潜在生物标志物。在血清循环 DNA 中检测这些基因的启动子甲基化状态是一种很有前途的早期检测胰腺癌的策略，有可能提高这种疾病的死亡率。
