DNA hypermethylation driven by DNMT1 and DNMT3A favors tumor immune escape contributing to the aggressiveness of adrenocortical carcinoma

Clinical Epigenetics

Research

Constanze Hantel¹  Jérôme Bertherat²  Gwenneg Kerdivel²  Juliette Hamroune²  Floriane Amrouche²  Guillaume Assié²  Marie-Ange Calmejane²  Valentina Boeva³  Floriane Carallis⁴ 

[1] Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), Zurich, Switzerland;Medizinische Klinik und Poliklinik III, University Hospital Carl Gustav Carus Dresden, Dresden, Germany;INSERM, U1016, Cochin Institute, CNRS UMR8104, University of Paris, 24 rue du Faubourg Saint-Jacques, Paris, France;INSERM, U1016, Cochin Institute, CNRS UMR8104, University of Paris, 24 rue du Faubourg Saint-Jacques, Paris, France;Department of Computer Science, Institute for Machine Learning, ETH Zurich, Universitätstrasse 6, 8092, Zurich, Switzerland;Swiss Institute of Bioinformatics (SIB), Zurich, Switzerland;Inovarion, Paris, France;

关键词: DNA methylation;    CIMP;    DNA methyltransferases;    DNMTs;    Demethylating agents;    5-azacytidine;    Adrenocortical carcinoma;    Immune escape;   

DOI  :  10.1186/s13148-023-01534-5

 received in 2022-08-01, accepted in 2023-07-16,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAdrenocortical 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.ResultsHere, 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.ConclusionsIn 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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