MGMT失活作为晚期胆道癌患者的一种新生物标志物

IF 5 2区医学 Q1 ONCOLOGY

Molecular Oncology Pub Date : 2022-05-27 DOI:10.1002/1878-0261.13256

M. Niger, F. Nichetti, A. Casadei‐Gardini, F. Morano, C. Pircher, E. Tamborini, F. Perrone, M. Canale, D. Lipka, A. Vingiani, L. Agnelli, A. Dobberkau, J. Hüllein, Felix Korell, C. Heilig, S. Pusceddu, F. Corti, M. Droz, P. Ulivi, M. Prisciandaro, M. Antista, M. Bini, L. Cattaneo, M. Milione, H. Glimm, B. Köhler, G. Pruneri, D. Hübschmann, S. Fröhling, V. Mazzaferro, F. Pietrantonio, M. Di Bartolomeo, F. de Braud

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引用次数: 3

摘要

胆道癌（BTCs）预后不良，治疗选择有限。O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）失活对晚期BTC患者的影响尚未确定。我们在两个多中心队列中调查了MGMT失活的患病率、预后和预测影响。在意大利队列中通过PCR和免疫组织化学（IHC）评估MGMT失活；然后使用来自海德堡国家肿瘤疾病中心和德国癌症联合会的分子辅助分层肿瘤根除研究（MASTER）精确肿瘤学计划的BTC子项的RNA测序（RNA-seq）数据对结果进行外部验证。在164例意大利病例中，18%的病例出现MGMT启动子超甲基化（> 14%）和73%具有阴性MGMT蛋白表达。两者均与较差的总生存率相关（OS；HR 2.31；P < 0.001和HR 1.99，P = 0.012）。在MASTER队列中，MGMT mRNA表达较低的患者表现出明显较差的OS（中位OS[mOS]20.4 vs 31.7 月，未调整HR 1.89；P = 0.043）。我们的研究结果表明，MGMT失活是BTC中一种常见的表观遗传学改变，具有显著的预后影响，并为探索MGMT灭活BTC中的DNA损伤因子提供了理论依据。

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MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers

Biliary tract cancers (BTCs) have poor prognosis and limited therapeutic options. The impact of O6‐methylguanine‐DNA methyltransferase (MGMT) inactivation in advanced BTC patients is not established. We investigated the prevalence, prognostic, and predictive impact of MGMT inactivation in two multicenter cohorts. MGMT inactivation was assessed through PCR and immunohistochemistry (IHC) in an Italian cohort; the results were then externally validated using RNA sequencing (RNA‐seq) data from the BTC subcohort of the Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program of the National Center for Tumor Diseases Heidelberg and the German Cancer Consortium. Among 164 Italian cases, 18% presented MGMT promoter hypermethylation (> 14%) and 73% had negative MGMT protein expression. Both were associated with worse overall survival (OS; HR 2.31; P < 0.001 and HR 1.99, P = 0.012, respectively). In the MASTER cohort, patients with lower MGMT mRNA expression showed significantly poorer OS (median OS [mOS] 20.4 vs 31.7 months, unadjusted HR 1.89; P = 0.043). Our results suggest that MGMT inactivation is a frequent epigenetic alteration in BTC, with a significant prognostic impact, and provide the rationale to explore DNA‐damaging agents in MGMT‐inactivated BTCs.

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来源期刊

Molecular Oncology 医学-肿瘤学

CiteScore

12.60

自引率

1.50%

发文量

203

审稿时长

6-12 weeks

期刊介绍： Molecular Oncology highlights new discoveries, approaches, and technical developments, in basic, clinical and discovery-driven translational cancer research. It publishes research articles, reviews (by invitation only), and timely science policy articles. The journal is now fully Open Access with all articles published over the past 10 years freely available.