This work examines differences in chromatin accessibility, methylation, and response to DNA hypomethylating agents between mismatch repair-deficient and non-mismatch repair-deficient endometrial cancer. Next-generation sequencing of a stage 1B, grade 2 endometrioid endometrial cancer tumor revealed microsatellite instability and a variant of unknown significance in POLE along with global and MLH1 hypermethylation. Inhibition of viability by decitabine in the study and comparison tumors was minimal, as shown by an inhibitory effect of 0 and 17.9, respectively. Conversely, the inhibitory effect of azacitidine on the study tumor was more pronounced, at 72.8 versus 41.2. In vitro, mismatch repair-deficient endometrial cancer with MLH1 hypermethylation respond better to DNA methyltransferase inhibition by azacytidine (DNA/RNA inhibition), than to decitabine (DNA-only inhibition). Additional large studies are needed to substantiate our findings.

Tweetable abstract

Epigenomic integration of mismatch repair-deficient hypermethylated endometrial cancer may explain differential invitro response to DNA hypomethylating agents.

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Vol. 15, No. 5

Supplemental Materials

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History

Received 25 January 2023

Accepted 24 April 2023

Published online 22 May 2023

Published in print March 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/epi-2023-0026

Author contributions

Conception: MT Barrett, MRS Walther-Antonio, JC Cheville, MJ Borad, AS Mansfield, SJ Murphy, A Mariani, G Vasmatzis, PZ Anastasiadis, SJ Weroha and AM Larish. Case review: G Cucinella, G Schivardi, A Mariani and AM Larish. Histology preparation and review: D Sadeghian, AF McCune, G Cucinella, A Mariani, SJ Weroha and AM Larish. Sample preparation for genomic and epigenomic sequencing: FR Harris. Pharmacological assessment: WH Lin, LM Kinsella and RW Feathers. Data analysis: LY El Khoury, JB Smadbeck, SH Johnson and A Bhagwate. Manuscript writing: LY El Khoury, WH Lin and AM Larish. All authors reviewed and approved the manuscript.

Acknowledgments

The authors would like to thank A Emmanuel and S Anderson for providing invaluable administrative support throughout the project.

Financial & competing interests disclosure

This project was funded by the Center for Individualized Medicine and Beyond DNA Strategic Focus Area at Mayo Clinic. AS Mansfield reports research support from Novartis and Verily Life Sciences; remuneration to his institution for participation on advisory boards for AbbVie, AstraZeneca, Bristol Myers Squibb, Genentech and Janssen; and travel support and payment from Shanghai Roche Pharmaceuticals Ltd. AS Mansfield is also an unremunerated director of the Mesothelioma Applied Research Foundation. G Vasmatzis is the owner of WholeGenome LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

All study activity was approved by the Mayo Clinic institutional review board. All patient identifiers were removed as appropriate in accordance with the Health Insurance Portability and Accountability Act. The authors state that they have obtained verbal and written informed consent from the patient/patients for the inclusion of their medical and treatment history within this case report.

Data sharing statement

The authors certify that this article reports original clinical trial data. The data will not be made publicly available but will be available upon request.

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