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Research Paper

LINE-1 methylation in plasma DNA as a biomarker of activity of DNA methylation inhibitors in patients with solid tumors

Ana Aparicio, Brittany North, Lindsey Barske, Xuemei Wang, Valentina Bollati, Daniel Weisenberger, Christine Yoo, Nizar Tannir, Erin Horne, Susan Groshen, Peter Jones, Allen Yang and Jean-Pierre Issa

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Multiple clinical trials are investigating the use of the DNA methylation inhibitors azacitidine and decitabine for the treatment of solid tumors. Clinical trials in hematological malignancies have shown that optimal activity does not occur at their maximum tolerated doses but selection of an optimal biological dose and schedule for use in solid tumor patients is hampered by the difficulty of obtaining tumor tissue to measure their activity. Here we investigate the feasibility of using plasma DNA to measure the demethylating activity of the DNA methylation inhibitors in patients with solid tumors. We compared four methods to measure LINE-1 and MAGE-A1 promoter methylation in T24 and HCT116 cancer cells treated with decitabine treatment and selected Pyrosequencing for its greater reproducibility and higher signal to noise ratio. We then obtained DNA from plasma, peripheral blood mononuclear cells, buccal mucosa cells and saliva from ten patients with metastatic solid tumors at two different time points, without any intervening treatment. DNA methylation measurements were not significantly different between time point 1 and time point 2 in patient samples. We conclude that measurement of LINE-1 methylation in DNA extracted from the plasma of patients with advanced solid tumors, using Pyrosequencing, is feasible and has low within patient variability. Ongoing studies will determine whether changes in LINE-1 methylation in plasma DNA occur as a result of treatment with DNA methylation inhibitors and parallel changes in tumor tissue DNA.

Authors

Ana Aparicio Corresponding author: aaparicio@mdanderson.org

University of Texas, MD Anderson Cancer Center

Brittany North

University of Texas, MD Anderson Cancer Center

Lindsey Barske

Duke University Medical Center

Xuemei Wang

University of Texas, MD Anderson Cancer Center

Valentina Bollati

University of Milan

Daniel Weisenberger

University of Southern California, Norris Comprehensive Cancer Center

Christine Yoo

University of Southern California, Norris Comprehensive Cancer Center

Nizar Tannir

University of Texas, MD Anderson Cancer Center

Erin Horne

University of Texas, MD Anderson Cancer Center

Susan Groshen

University of Southern California, Norris Comprehensive Cancer Center

Peter Jones

Norris Comprehensive Cancer Center, University of Southern California

Allen Yang

University of Southern California, Norris Comprehensive Cancer Center

Jean-Pierre Issa

University of Texas, MD Anderson Cancer Center

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.