DNA Hypermethylation Driven by DNMT1 and DNMT3A Favors Tumor Immune Escape Contributing to the Aggressiveness of Adrenocortical Carcinoma

Overview

Journal Clin Epigenetics

Publisher Biomed Central

Specialty Genetics

Date 2023 Aug 1

PMID 37528470

Authors

Gwenneg Kerdivel

Floriane Amrouche

Marie-Ange Calmejane

Floriane Carallis

Juliette Hamroune

Constanze Hantel

Jerome Bertherat

Guillaume Assie

Valentina Boeva

Affiliations

Soon will be listed here.

Abstract

Background: Adrenocortical carcinoma is rare and aggressive endocrine cancer of the adrenal gland. Within adrenocortical carcinoma, a recently described subtype characterized by a CpG island methylator phenotype (CIMP) has been associated with an especially poor prognosis. However, the drivers of CIMP remain unknown. Furthermore, the functional relation between CIMP and poor clinical outcomes of patients with adrenocortical carcinoma stays elusive.

Results: Here, we show that CIMP in adrenocortical carcinoma is linked to the increased expression of DNA methyltransferases DNMT1 and DNMT3A driven by a gain of gene copy number and cell hyperproliferation. Importantly, we demonstrate that CIMP contributes to tumor aggressiveness by favoring tumor immune escape. This effect could be at least partially reversed by treatment with the demethylating agent 5-azacytidine.

Conclusions: In sum, our findings suggest that co-treatment with demethylating agents might enhance the efficacy of immunotherapy and could represent a novel therapeutic approach for patients with high CIMP adrenocortical carcinoma.

Citing Articles

A Database Tool Integrating Genomic and Pharmacologic Data from Adrenocortical Carcinoma Cell Lines, PDX, and Patient Samples.

Arakawa Y, Elloumi F, Varma S, Khandagale P, Jo U, Kumar S Cancer Res Commun. 2024; 4(9):2384-2398.

PMID: 39162009 PMC: 11389377. DOI: 10.1158/2767-9764.CRC-24-0100.

Correlation between the RNA Expression and the DNA Methylation of Estrogen Receptor Genes in Normal and Malignant Human Tissues.

Rong J, Xie X, Niu Y, Su Z Curr Issues Mol Biol. 2024; 46(4):3610-3625.

PMID: 38666956 PMC: 11049367. DOI: 10.3390/cimb46040226.

DNMT1-mediated epigenetic suppression of FBXO32 expression promoting cyclin dependent kinase 9 (CDK9) survival and esophageal cancer cell growth.

Song X, Chen B, Jin Y, Wang C Cell Cycle. 2024; 23(3):262-278.

PMID: 38597826 PMC: 11057636. DOI: 10.1080/15384101.2024.2309022.

References

Nie Y, Yang G, Song Y, Zhao X, So C, Liao J . DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human esophageal squamous cell carcinomas. Carcinogenesis. 2001; 22(10):1615-23. DOI: 10.1093/carcin/22.10.1615. View

Gyorffy B, Bottai G, Fleischer T, Munkacsy G, Budczies J, Paladini L . Aberrant DNA methylation impacts gene expression and prognosis in breast cancer subtypes. Int J Cancer. 2015; 138(1):87-97. DOI: 10.1002/ijc.29684. View

Pellacani D, Kestoras D, Droop A, Frame F, Berry P, Lawrence M . DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation. Cell Death Differ. 2014; 21(5):761-73. PMC: 3978305. DOI: 10.1038/cdd.2013.202. View

Wrangle J, Wang W, Koch A, Easwaran H, Mohammad H, Vendetti F . Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Oncotarget. 2013; 4(11):2067-79. PMC: 3875770. DOI: 10.18632/oncotarget.1542. View

Varghese J, Habra M . Update on adrenocortical carcinoma management and future directions. Curr Opin Endocrinol Diabetes Obes. 2017; 24(3):208-214. DOI: 10.1097/MED.0000000000000332. View

Risso D, Ngai J, Speed T, Dudoit S . Normalization of RNA-seq data using factor analysis of control genes or samples. Nat Biotechnol. 2014; 32(9):896-902. PMC: 4404308. DOI: 10.1038/nbt.2931. View

Robertson K, Keyomarsi K, Gonzales F, Velicescu M, Jones P . Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res. 2000; 28(10):2108-13. PMC: 105379. DOI: 10.1093/nar/28.10.2108. View

Spencer D, Russler-Germain D, Ketkar S, Helton N, Lamprecht T, Fulton R . CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression. Cell. 2017; 168(5):801-816.e13. PMC: 5328582. DOI: 10.1016/j.cell.2017.01.021. View

Ye Q, Shen Y, Wang X, Yang J, Miao F, Shen C . Hypermethylation of HLA class I gene is associated with HLA class I down-regulation in human gastric cancer. Tissue Antigens. 2009; 75(1):30-9. DOI: 10.1111/j.1399-0039.2009.01390.x. View

10.

Zheng S, Cherniack A, Dewal N, Moffitt R, Danilova L, Murray B . Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. Cancer Cell. 2016; 29(5):723-736. PMC: 4864952. DOI: 10.1016/j.ccell.2016.04.002. View

11.

Guo W, Fiziev P, Yan W, Cokus S, Sun X, Zhang M . BS-Seeker2: a versatile aligning pipeline for bisulfite sequencing data. BMC Genomics. 2013; 14:774. PMC: 3840619. DOI: 10.1186/1471-2164-14-774. View

12.

Issa J . CpG island methylator phenotype in cancer. Nat Rev Cancer. 2004; 4(12):988-93. DOI: 10.1038/nrc1507. View

13.

McCormick K, Ghosh A, Trivedi S, Wang L, Coyne C, Ferris R . Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous cell carcinoma. Carcinogenesis. 2016; 37(5):522-9. PMC: 6086476. DOI: 10.1093/carcin/bgw032. View

14.

Saghafinia S, Mina M, Riggi N, Hanahan D, Ciriello G . Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors. Cell Rep. 2018; 25(4):1066-1080.e8. DOI: 10.1016/j.celrep.2018.09.082. View

15.

Assie G, Letouze E, Fassnacht M, Jouinot A, Luscap W, Barreau O . Integrated genomic characterization of adrenocortical carcinoma. Nat Genet. 2014; 46(6):607-12. DOI: 10.1038/ng.2953. View

16.

Amankulor N, Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M . Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes Dev. 2017; 31(8):774-786. PMC: 5435890. DOI: 10.1101/gad.294991.116. View

17.

Fiorentini C, Grisanti S, Cosentini D, Abate A, Rossini E, Berruti A . Molecular Drivers of Potential Immunotherapy Failure in Adrenocortical Carcinoma. J Oncol. 2019; 2019:6072863. PMC: 6463568. DOI: 10.1155/2019/6072863. View

18.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

19.

Figueroa M, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos P . DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010; 17(1):13-27. PMC: 3008568. DOI: 10.1016/j.ccr.2009.11.020. View

20.

Andersen C, Jensen J, Orntoft T . Normalization of real-time quantitative reverse transcription-PCR data: a model-based variance estimation approach to identify genes suited for normalization, applied to bladder and colon cancer data sets. Cancer Res. 2004; 64(15):5245-50. DOI: 10.1158/0008-5472.CAN-04-0496. View