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, Christine A. Iacobuzio-Donahue, Ralph H. Hruban, Jin He, Tza Huei Wang, Laura D. WoodAnup Sharma, Nita Ahuja

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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.

Original languageEnglish (US)
Article number59
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
StatePublished - Apr 5 2019

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Keywords

  • ADAMTS1
  • BNC1
  • Biomarker
  • Cell-free DNA
  • MOB
  • Methylation
  • Pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Developmental Biology
  • Genetics(clinical)

Cite this

Eissa, M. A. L., Lerner, L., Abdelfatah, E., Shankar, N., Canner, J. K., Hasan, N. M., Yaghoobi, V., Huang, B., Kerner, Z., Takaesu, F., Wolfgang, C., Kwak, R., Ruiz, M., Tam, M., Pisanic, T. R., Iacobuzio-Donahue, C. A., Hruban, R. H., He, J., Wang, T. H., ... Ahuja, N. (2019). Promoter methylation of ADAMTS1 and BNC1 as potential biomarkers for early detection of pancreatic cancer in blood. Clinical Epigenetics, 11(1), [59]. https://doi.org/10.1186/s13148-019-0650-0