TY - JOUR
T1 - Discovery, validation, and application of novel methylated DNA markers for detection of esophageal cancer in plasma
AU - Qin, Yi
AU - Wu, Chung W.
AU - Taylor, William R.
AU - Sawas, Tarek
AU - Burger, Kelli N.
AU - Mahoney, Douglas W.
AU - Sun, Zhifu
AU - Yab, Tracy C.
AU - Lidgard, Graham P.
AU - Allawi, Hatim T.
AU - Buttar, Navtej S.
AU - Smyrk, Thomas C.
AU - Iyer, Prasad G.
AU - Katzka, David A.
AU - Ahlquist, David A.
AU - Kisiel, John B.
N1 - Funding Information:
This work was supported by the Maxine and Jack Zarrow Family Foundation of Tulsa Oklahoma (to JBK), R37CA214679 (to JBK), a gift from Eddie Gong and Dana Clay (to DAA), the Carol M. Gatton endowment for Digestive Diseases Research (to DAA). This publication was also made possible by UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS). RRBS sequencing costs and QuARTS assays were provided by Exact Sciences (Madison WI).
Funding Information:
W.R. Taylor reports receiving commercial research grants from and holds ownership interest (including patents) in Exact Sciences. D.W. Mahoney holds ownership interest (including patents) in Exact Sciences. T.C. Yab holds ownership interest (including patents) in Exact Sciences. G.P. Lidgard is an employee/paid consultant for Exact Sciences. H.T. Allawi is an employee/paid consultant for Exact Sciences. P.G. Iyer reports receiving commercial research grants from Exact Sciences; reports receiving other commercial research support from Pentax Medical; and is an unpaid consultant/advisory board member for Medtronic and Symple Surgical. D.A. Katzka reports receiving speakers bureau honoraria from Celgene. D.A. Ahlquist reports receiving commercial research grants from, holds ownership interest (including patents) in, and is an unpaid consultant/advisory board member for Exact Sciences. J.B. Kisiel reports receiving other commercial research support from and holds ownership interest (including patents) in Exact Sciences. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019/12/15
Y1 - 2019/12/15
N2 - Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma. Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping. Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index. Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
AB - Purpose: The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma. Experimental Design: Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping. Results: From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index. Conclusions: Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
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U2 - 10.1158/1078-0432.CCR-19-0740
DO - 10.1158/1078-0432.CCR-19-0740
M3 - Article
C2 - 31527170
AN - SCOPUS:85076503310
SN - 1078-0432
VL - 25
SP - 7396
EP - 7403
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -