Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer

Louis Y. El Khoury; Wan Hsin Lin; James B. Smadbeck; Michael T. Barrett; Dorsay Sadeghian; Alexa F. Mccune; Giannoula Karagouga; John C. Cheville; Faye R. Harris; Lindsey M. Kinsella; Ryan W. Feathers; Janet L. Schafer Klein; Marina R.S. Walther-Antonio; Sarah H. Johnson; Alan R. Penheiter; Giuseppe Cucinella; Gabriella Schivardi; Aditya Bhagwate; Mitesh J. Borad; Aaron S. Mansfield; Stephen J. Murphy; Andrea Mariani; George Vasmatzis; Panos Z. Anastasiadis; Saravut J. Weroha; Alyssa M. Larish

doi:10.2217/epi-2023-0026

Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer

Louis Y. El Khoury, Wan Hsin Lin, James B. Smadbeck, Michael T. Barrett, Dorsay Sadeghian, Alexa F. Mccune, Giannoula Karagouga, John C. Cheville, Faye R. Harris, Lindsey M. Kinsella, Ryan W. Feathers, Janet L. Schafer Klein, Marina R.S. Walther-Antonio, Sarah H. Johnson, Alan R. Penheiter, Giuseppe Cucinella, Gabriella Schivardi, Aditya Bhagwate, Mitesh J. Borad, Aaron S. MansfieldStephen J. Murphy, Andrea Mariani, George Vasmatzis, Panos Z. Anastasiadis, Saravut J. Weroha, Alyssa M. Larish

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	283-292
Number of pages	10
Journal	Epigenomics
Volume	15
Issue number	5
DOIs	https://doi.org/10.2217/epi-2023-0026
State	Published - Mar 1 2023

Keywords

DNA methylation
azacitidine
decitabine
endometrial cancer
epigenomics
mismatch repair

ASJC Scopus subject areas

Genetics
Cancer Research

Access to Document

10.2217/epi-2023-0026

Cite this

El Khoury, L. Y., Lin, W. H., Smadbeck, J. B., Barrett, M. T., Sadeghian, D., Mccune, A. F., Karagouga, G., Cheville, J. C., Harris, F. R., Kinsella, L. M., Feathers, R. W., Schafer Klein, J. L., Walther-Antonio, M. R. S., Johnson, S. H., Penheiter, A. R., Cucinella, G., Schivardi, G., Bhagwate, A., Borad, M. J., ... Larish, A. M. (2023). Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer. Epigenomics, 15(5), 283-292. https://doi.org/10.2217/epi-2023-0026

El Khoury, LY, Lin, WH, Smadbeck, JB , Barrett, MT, Sadeghian, D, Mccune, AF, Karagouga, G, Cheville, JC, Harris, FR, Kinsella, LM, Feathers, RW, Schafer Klein, JL, Walther-Antonio, MRS, Johnson, SH, Penheiter, AR, Cucinella, G, Schivardi, G, Bhagwate, A, Borad, MJ , Mansfield, AS , Murphy, SJ, Mariani, A, Vasmatzis, G , Anastasiadis, PZ , Weroha, SJ & Larish, AM 2023, 'Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer', Epigenomics, vol. 15, no. 5, pp. 283-292. https://doi.org/10.2217/epi-2023-0026

@article{2eff23450c50480896ecb4b1cd6789e3,

title = "Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer",

abstract = "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.",

keywords = "DNA methylation, azacitidine, decitabine, endometrial cancer, epigenomics, mismatch repair",

author = "{El Khoury}, {Louis Y.} and Lin, {Wan Hsin} and Smadbeck, {James B.} and Barrett, {Michael T.} and Dorsay Sadeghian and Mccune, {Alexa F.} and Giannoula Karagouga and Cheville, {John C.} and Harris, {Faye R.} and Kinsella, {Lindsey M.} and Feathers, {Ryan W.} and {Schafer Klein}, {Janet L.} and Walther-Antonio, {Marina R.S.} and Johnson, {Sarah H.} and Penheiter, {Alan R.} and Giuseppe Cucinella and Gabriella Schivardi and Aditya Bhagwate and Borad, {Mitesh J.} and Mansfield, {Aaron S.} and Murphy, {Stephen J.} and Andrea Mariani and George Vasmatzis and Anastasiadis, {Panos Z.} and Weroha, {Saravut J.} and Larish, {Alyssa M.}",

note = "Publisher Copyright: {\textcopyright} 2023 Future Medicine Ltd.",

year = "2023",

month = mar,

day = "1",

doi = "10.2217/epi-2023-0026",

language = "English (US)",

volume = "15",

pages = "283--292",

journal = "Epigenomics",

issn = "1750-1911",

publisher = "Taylor and Francis Ltd.",

number = "5",

}

TY - JOUR

T1 - Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer

AU - El Khoury, Louis Y.

AU - Lin, Wan Hsin

AU - Smadbeck, James B.

AU - Barrett, Michael T.

AU - Sadeghian, Dorsay

AU - Mccune, Alexa F.

AU - Karagouga, Giannoula

AU - Cheville, John C.

AU - Harris, Faye R.

AU - Kinsella, Lindsey M.

AU - Feathers, Ryan W.

AU - Schafer Klein, Janet L.

AU - Walther-Antonio, Marina R.S.

AU - Johnson, Sarah H.

AU - Penheiter, Alan R.

AU - Cucinella, Giuseppe

AU - Schivardi, Gabriella

AU - Bhagwate, Aditya

AU - Borad, Mitesh J.

AU - Mansfield, Aaron S.

AU - Murphy, Stephen J.

AU - Mariani, Andrea

AU - Vasmatzis, George

AU - Anastasiadis, Panos Z.

AU - Weroha, Saravut J.

AU - Larish, Alyssa M.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - 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.

AB - 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.

KW - DNA methylation

KW - azacitidine

KW - decitabine

KW - endometrial cancer

KW - epigenomics

KW - mismatch repair

UR - http://www.scopus.com/inward/record.url?scp=85160877991&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85160877991&partnerID=8YFLogxK

U2 - 10.2217/epi-2023-0026

DO - 10.2217/epi-2023-0026

M3 - Article

C2 - 37212177

AN - SCOPUS:85160877991

SN - 1750-1911

VL - 15

SP - 283

EP - 292

JO - Epigenomics

JF - Epigenomics

IS - 5

ER -

Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this