Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer

• Published in: Clinical cancer research 2013-12, Vol.19 (23), p.6544-6555
• Main Authors: JOO MI YI, GUZZETTA, Angela A, PAPPOU, Emmanouil P, LACOBUZIO-DONAHUE, Christine A, GOGGINS, Michael G, HERMAN, James G, WANG, Tza-Huei, BAYLIN, Stephen B, AHUJA, Nita, BAILEY, Vasudev J, DOWNING, Stephanie R, VAN NESTE, Leander, CHIAPPINELLI, Katherine B, KEELEY, Brian P, STARK, Alejandro, HERRERA, Alexander, WOLFGANG, Christopher
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAMTS1 Protein; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - genetics; Carcinoma in Situ - diagnosis; Carcinoma in Situ - genetics; Carcinoma in Situ - mortality; Cell Line, Tumor; Cell Movement; Cell Proliferation; CpG Islands; DNA - blood; DNA - genetics; DNA Methylation; DNA-Binding Proteins - genetics; Early Detection of Cancer; Epigenesis, Genetic; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Molecular Diagnostic Techniques; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Pancreatic Neoplasms - diagnosis; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Pharmacology. Drug treatments; Promoter Regions, Genetic; Proportional Hazards Models; Sensitivity and Specificity; Sequence Analysis, DNA; Transcription Factors - genetics; Transcriptome; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-3224

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.