Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms Journal Article
| Authors: | Chhoda, A.; Sharma, A.; Sailo, B.; Tang, H.; Ruzgar, N.; Tan, W. Y.; Ying, L.; Khatri, R.; Narayanan, A.; Mane, S.; De Kumar, B.; Wood, L. D.; Iacobuzio-Donahue, C.; Wolfgang, C. L.; Kunstman, J. W.; Salem, R. R.; Farrell, J. J.; Ahuja, N. |
| Article Title: | Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms |
| Abstract: | BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs), a type of cystic pancreatic cancer (PC) precursors, are increasingly identified on cross-sectional imaging and present a significant diagnostic challenge. While surgical resection of IPMN-related advanced neoplasia, i.e., IPMN-related high-grade dysplasia or PC, is an essential early PC detection strategy, resection is not recommended for IPMN-low-grade dysplasia (LGD) due to minimal risk of carcinogenesis, and significant procedural risks. Based on their promising results in prior validation studies targeting early detection of classical PC, DNA hypermethylation-based markers may serve as a biomarker for malignant risk stratification of IPMNs. This study investigates our DNA methylation-based PC biomarker panel (ADAMTS1, BNC1, and CACNA1G genes) in differentiating IPMN-advanced neoplasia from IPMN-LGDs. METHODS: Our previously described genome-wide pharmaco-epigenetic method identified multiple genes as potential targets for PC detection. The combination was further optimized and validated for early detection of classical PC in previous case-control studies. These promising genes were evaluated among micro-dissected IPMN tissue (IPMN-LGD: 35, IPMN-advanced neoplasia: 35) through Methylation-Specific PCR. The discriminant capacity of individual and combination of genes were delineated through Receiver Operating Characteristics curve analysis. RESULTS: As compared to IPMN-LGDs, IPMN-advanced neoplasia had higher hypermethylation frequency of candidate genes: ADAMTS1 (60% vs. 14%), BNC1 (66% vs. 3%), and CACGNA1G (25% vs. 0%). We observed Area Under Curve (AUC) values of 0.73 for ADAMTS1, 0.81 for BNC1, and 0.63 for CACNA1G genes. The combination of the BNC1/ CACNA1G genes resulted in an AUC of 0.84, sensitivity of 71%, and specificity of 97%. Combining the methylation status of the BNC1/CACNA1G genes, blood-based CA19-9, and IPMN lesion size enhanced the AUC to 0.92. CONCLUSION: DNA-methylation based biomarkers have shown a high diagnostic specificity and moderate sensitivity for differentiating IPMN-advanced neoplasia from LGDs. Addition of specific methylation targets can improve the accuracy of the methylation biomarker panel and enable the development of noninvasive IPMN stratification biomarkers. © 2023. The Author(s). |
| Keywords: | genetics; pancreatic neoplasms; neoplasm; pathology; tumor marker; dna methylation; risk assessment; dna; pancreas tumor; pancreatic cancer; pancreatic cyst; neoplasms, cystic, mucinous, and serous; humans; human; biomarkers, tumor; pancreatic intraductal neoplasms; methylation-specific biomarker |
| Journal Title: | Clinical Epigenetics |
| Volume: | 15 |
| ISSN: | 1868-7075 |
| Publisher: | BioMed Central Ltd. |
| Date Published: | 2023-02-20 |
| Start Page: | 28 |
| Language: | English |
| DOI: | 10.1186/s13148-023-01429-5 |
| PUBMED: | 36803844 |
| PROVIDER: | scopus |
| PMCID: | PMC9942382 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2023 -- Source: Scopus |
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