Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood

Maryam A L Eissa, Lane Lerner, Eihab Abdelfatah, Nakul Shankar, Joseph K Canner, Nesrin M Hasan, Vesal Yaghoobi, Barry Huang, Zachary Kerner, Felipe Takaesu, Christopher Wolfgang, Ruby Kwak, Michael Ruiz, Matthew Tam, Thomas R Pisanic 2nd, Christine A Iacobuzio-Donahue, Ralph H Hruban, Jin He, Tza-Huei Wang, Laura D Wood, Anup Sharma, Nita Ahuja, Maryam A L Eissa, Lane Lerner, Eihab Abdelfatah, Nakul Shankar, Joseph K Canner, Nesrin M Hasan, Vesal Yaghoobi, Barry Huang, Zachary Kerner, Felipe Takaesu, Christopher Wolfgang, Ruby Kwak, Michael Ruiz, Matthew Tam, Thomas R Pisanic 2nd, Christine A Iacobuzio-Donahue, Ralph H Hruban, Jin He, Tza-Huei Wang, Laura D Wood, Anup Sharma, Nita Ahuja

Abstract

Background: Despite improvements in cancer management, most pancreatic cancers are still diagnosed at an advanced stage. We have recently identified promoter DNA methylation of the genes ADAMTS1 and BNC1 as potential blood biomarkers of pancreas cancer. In this study, we validate this biomarker panel in peripheral cell-free tumor DNA of patients with pancreatic cancer.

Results: Sensitivity and specificity for each gene are as follows: ADAMTS1 87.2% and 95.8% (AUC = 0.91; 95% CI 0.71-0.86) and BNC1 64.1% and 93.7% (AUC = 0.79; 95% CI 0.63-0.78). When using methylation of either gene as a combination panel, sensitivity increases to 97.3% and specificity to 91.6% (AUC = 0.95; 95% CI 0.77-0.90). Adding pre-operative CA 19-9 values to the combined two-gene methylation panel did not improve sensitivity. Methylation of ADAMTS1 was found to be positive in 87.5% (7/8) of stage I, 77.8% (7/9) of stage IIA, and 90% (18/20) of stage IIB disease. Similarly, BNC1 was positive in 62.5% (5/8) of stage I patients, 55.6% (5/9) of stage IIA, and 65% (13/20) of patients with stage IIB disease. The two-gene panel (ADAMTS1 and/or BNC1) was positive in 100% (8/8) of stage I, 88.9% (8/9) of stage IIA, and 100% (20/20) of stage IIB disease. The sensitivity and specificity of the two-gene panel for localized pancreatic cancer (stages I and II), where the cancer is eligible for surgical resection with curative potential, was 94.8% and 91.6% respectively. Additionally, the two-gene panel exhibited an AUC of 0.95 (95% CI 0.90-0.98) compared to 57.1% for CA 19-9 alone.

Conclusion: The methylation status of ADAMTS1 and BNC1 in cfDNA shows promise for detecting pancreatic cancer during the early stages when curative resection of the tumor is still possible. This minimally invasive blood-based biomarker panel could be used as a promising tool for diagnosis and screening in a select subset of high-risk populations.

Keywords: ADAMTS1; BNC1; Biomarker; Cell-free DNA; MOB; Methylation; Pancreatic cancer.

Conflict of interest statement

Ethics approval and consent to participate

The Institutional Review Boards of Johns Hopkins University approved the present study. In addition, blood samples were collected and analyzed as per institutional IRB protocol (NA00033085).

Consent for publication

Not applicable

Competing interests

NA has received grant funding from Cepheid and Astex and has served as a consultant to Ethicon. NA has licensed methylation Biomarkers (BNC1 and ADAMTS1) to Cepheid Inc. All other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Methylation of ADAMTS1 and BNC1 genes in control and PDAC cases
Fig. 2
Fig. 2
Sensitivity and specificity of both genes. ROC curves for various genes. (a, b) ROC curves are represented for individual genes (ADAMTS1 and BNC1) and c combined methylation status of the genes (ADAMTS1 + BNC1) from the plasma samples

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