Detection of gastric cancer with novel methylated DNA markers: Discovery, tissue validation, and pilot testing in plasma

Bradley W. Anderson, Yun Suhk Suh, Boram Choi, Hyuk Joon Lee, Tracy C. Yab, William R. Taylor, Brian A. Dukek, Calise K. Berger, Xiaoming Cao, Patrick H. Foote, Mary E. Devens, Lisa Allyn Boardman, John B Kisiel, Douglas W. Mahoney, Seth W. Slettedahl, Hatim T. Allawi, Graham P. Lidgard, Thomas Christopher Smyrk, Han Kwang Yang, David A. Ahlquist

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls. Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case–control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls. Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92% to 100% of U.S. and South Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI, 71–95) of gastric adenocarcinomas at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted.

Original languageEnglish (US)
Pages (from-to)5724-5734
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number22
DOIs
StatePublished - Nov 15 2018

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Genetic Markers
Stomach Neoplasms
Stomach
Adenocarcinoma
Methylation
Metaplasia
Adenoma
Carcinogenesis
Mucous Membrane
Research Design
Alleles
Polymerase Chain Reaction
Mortality

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Anderson, B. W., Suh, Y. S., Choi, B., Lee, H. J., Yab, T. C., Taylor, W. R., ... Ahlquist, D. A. (2018). Detection of gastric cancer with novel methylated DNA markers: Discovery, tissue validation, and pilot testing in plasma. Clinical Cancer Research, 24(22), 5724-5734. https://doi.org/10.1158/1078-0432.CCR-17-3364

Detection of gastric cancer with novel methylated DNA markers : Discovery, tissue validation, and pilot testing in plasma. / Anderson, Bradley W.; Suh, Yun Suhk; Choi, Boram; Lee, Hyuk Joon; Yab, Tracy C.; Taylor, William R.; Dukek, Brian A.; Berger, Calise K.; Cao, Xiaoming; Foote, Patrick H.; Devens, Mary E.; Boardman, Lisa Allyn; Kisiel, John B; Mahoney, Douglas W.; Slettedahl, Seth W.; Allawi, Hatim T.; Lidgard, Graham P.; Smyrk, Thomas Christopher; Yang, Han Kwang; Ahlquist, David A.

In: Clinical Cancer Research, Vol. 24, No. 22, 15.11.2018, p. 5724-5734.

Research output: Contribution to journalArticle

Anderson, BW, Suh, YS, Choi, B, Lee, HJ, Yab, TC, Taylor, WR, Dukek, BA, Berger, CK, Cao, X, Foote, PH, Devens, ME, Boardman, LA, Kisiel, JB, Mahoney, DW, Slettedahl, SW, Allawi, HT, Lidgard, GP, Smyrk, TC, Yang, HK & Ahlquist, DA 2018, 'Detection of gastric cancer with novel methylated DNA markers: Discovery, tissue validation, and pilot testing in plasma', Clinical Cancer Research, vol. 24, no. 22, pp. 5724-5734. https://doi.org/10.1158/1078-0432.CCR-17-3364
Anderson, Bradley W. ; Suh, Yun Suhk ; Choi, Boram ; Lee, Hyuk Joon ; Yab, Tracy C. ; Taylor, William R. ; Dukek, Brian A. ; Berger, Calise K. ; Cao, Xiaoming ; Foote, Patrick H. ; Devens, Mary E. ; Boardman, Lisa Allyn ; Kisiel, John B ; Mahoney, Douglas W. ; Slettedahl, Seth W. ; Allawi, Hatim T. ; Lidgard, Graham P. ; Smyrk, Thomas Christopher ; Yang, Han Kwang ; Ahlquist, David A. / Detection of gastric cancer with novel methylated DNA markers : Discovery, tissue validation, and pilot testing in plasma. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 22. pp. 5724-5734.
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abstract = "Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls. Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case–control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls. Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92{\%} to 100{\%} of U.S. and South Korean cohorts at 100{\%} specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86{\%} (95{\%} CI, 71–95) of gastric adenocarcinomas at 95{\%} specificity. Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted.",
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T1 - Detection of gastric cancer with novel methylated DNA markers

T2 - Discovery, tissue validation, and pilot testing in plasma

AU - Anderson, Bradley W.

AU - Suh, Yun Suhk

AU - Choi, Boram

AU - Lee, Hyuk Joon

AU - Yab, Tracy C.

AU - Taylor, William R.

AU - Dukek, Brian A.

AU - Berger, Calise K.

AU - Cao, Xiaoming

AU - Foote, Patrick H.

AU - Devens, Mary E.

AU - Boardman, Lisa Allyn

AU - Kisiel, John B

AU - Mahoney, Douglas W.

AU - Slettedahl, Seth W.

AU - Allawi, Hatim T.

AU - Lidgard, Graham P.

AU - Smyrk, Thomas Christopher

AU - Yang, Han Kwang

AU - Ahlquist, David A.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - Purpose: Gastric adenocarcinoma is the third most common cause of cancer mortality worldwide. Accurate and affordable noninvasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDM) for gastric adenocarcinoma, validate their discrimination for gastric adenocarcinoma in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from gastric adenocarcinoma cases and normal controls. Experimental Design: Following discovery by unbiased whole-methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case–control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from gastric adenocarcinoma cases and normal controls. Results: Whole-methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected gastric adenocarcinoma in 92% to 100% of U.S. and South Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and gastric adenocarcinoma with variation in points of greatest marker acquisition. In plasma, a 3-marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI, 71–95) of gastric adenocarcinomas at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate gastric adenocarcinoma from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for gastric adenocarcinoma screening and surveillance is warranted.

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