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

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-08-02 DOI:10.1186/s13148-023-01534-5
Gwenneg Kerdivel, Floriane Amrouche, Marie-Ange Calmejane, Floriane Carallis, Juliette Hamroune, Constanze Hantel, Jérôme Bertherat, Guillaume Assié, Valentina Boeva
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引用次数: 1

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.

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DNMT1和DNMT3A驱动的DNA高甲基化有利于肿瘤免疫逃逸,有助于肾上腺皮质癌的侵袭性。
背景:肾上腺皮质癌是一种罕见的侵袭性肾上腺内分泌癌。在肾上腺皮质癌中,最近描述的一种以CpG岛甲基化表型(CIMP)为特征的亚型与特别差的预后相关。然而,CIMP的驱动因素仍然未知。此外,CIMP与肾上腺皮质癌患者临床预后不良之间的功能关系尚不明确。结果:在这里,我们发现CIMP在肾上腺皮质癌中与DNA甲基转移酶DNMT1和DNMT3A的表达增加有关,这是由基因拷贝数的增加和细胞过度增殖驱动的。重要的是,我们证明了CIMP通过促进肿瘤免疫逃逸来促进肿瘤的侵袭性。用去甲基化剂5-氮杂胞苷治疗至少可以部分逆转这种效应。结论:总之,我们的研究结果表明,与去甲基化药物联合治疗可能会提高免疫治疗的疗效,并可能为高CIMP肾上腺皮质癌患者提供一种新的治疗方法。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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