TY - JOUR
T1 - Utility of promoter hypermethylation in malignant risk stratification of intraductal papillary mucinous neoplasms
AU - Chhoda, Ankit
AU - Sharma, Anup
AU - Sailo, Bethsebie
AU - Tang, Haoyu
AU - Ruzgar, Nensi
AU - Tan, Wan Ying
AU - Ying, Lee
AU - Khatri, Rishabh
AU - Narayanan, Anand
AU - Mane, Shrikant
AU - De Kumar, Bony
AU - Wood, Laura Delong
AU - Iacobuzio-Donahue, Christine
AU - Wolfgang, Christopher L.
AU - Kunstman, John W.
AU - Salem, Ronald R.
AU - Farrell, James J.
AU - Ahuja, Nita
N1 - Funding Information:
N.A. receives research grant funding from Astex Inc and the Van Andel Research Institute. She is a consultant for and has licensed methylation biomarkers to Cepheid (patent # 10167513). N.A. has served as a consultant to Johnson and Johnson, an advisor to Celgene, and a member of the Scientific Advisory Council to the No Stomach for Cancer Foundation. N.A. also serves as PI on NIH grants 5P30CA016359-42 and 7R01CA185357-05. This work was supported by the NIH grant 7R01CA185357-05, NIH Research Grant P30CA016359 & Yale Cancer Center (YCGA pilot grant).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
KW - Methylation-specific biomarker
KW - Pancreatic cancer
KW - Pancreatic cyst
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U2 - 10.1186/s13148-023-01429-5
DO - 10.1186/s13148-023-01429-5
M3 - Article
C2 - 36803844
AN - SCOPUS:85148391643
SN - 1868-7075
VL - 15
JO - Clinical Epigenetics
JF - Clinical Epigenetics
IS - 1
M1 - 28
ER -