Nichetti Federico, Silvestri Marco, Agnelli Luca, Franza Andrea, Pircher Chiara, Rota Simone, Ambrosini Paolo, Fotia Giuseppe, Hüllein Jennifer, Randon Giovanni, Lajer Panna, Perrone Federica, Tamborini Elena, Leoncini Giuseppe, Coppa Jorgelina, Busset Michele Droz Dit, Pusceddu Sara, Milione Massimo, Morano Federica, Pietrantonio Filippo, Pruneri Giancarlo, Mazzaferro Vincenzo, Lipka Daniel B, Köhler Bruno Christian, Hübschmann Daniel, Fröhling Stefan, de Braud Filippo, Niger Monica
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Computational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cancer Med. 2024 Dec;13(23):e70393. doi: 10.1002/cam4.70393.
The identification of actionable molecular targets of pancreatic cancer (PAC) is key to improving patient outcomes. We hypothesized O6-methylguanine-DNA methyltransferase (MGMT) silencing may occur in a subset of PAC tumors, with unexplored clinical and molecular correlates.
We leveraged sequencing data from The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium 3 (CPTAC-3), and the (Australian Pancreatic Cancer Genome Initiative) PACA-AU cohorts to characterize MGMT-silenced PAC. Genomic, transcriptomic, methylation, and clinical data were investigated, and findings were validated in silico using methylation, transcriptomic and drug sensitivity data from Cancer Cell Line Encyclopedia (CCLE) project, and in a real-world cohort of PAC patients profiled for MGMT status at Istituto Nazionale Tumori of Milan (INT).
On the basis of Human Methylation 450k data, MGMT silencing was identified in ~6% of PAC cases and was enriched in tumors with non-ductal histology, with a trend toward longer overall survival. MGMT-silenced tumors were associated with a lower frequency of KRAS mutations and showed features of immune exclusion. In the INT cohort, MGMT-silencing was confirmed in ~7% of cases and prevalent in KRAS wild type tumors, with a favorable prognostic impact. In silico analysis suggested a higher sensitivity to alkylating and DNA damaging agents in MGMT-silenced PAC cell lines.
MGMT silencing occurs in a small subgroup of PACs and is enriched in KRAS wild type cases, with a favorable prognostic impact. Our findings provide the rationale to explore combinations of alkylating with DNA damaging agents in MGMT-silenced PAC.
确定胰腺癌（PAC）的可操作分子靶点是改善患者预后的关键。我们推测O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）沉默可能发生在一部分PAC肿瘤中，且存在尚未探索的临床和分子关联。
我们利用来自癌症基因组图谱（TCGA）、临床蛋白质组肿瘤分析联盟3（CPTAC-3）以及（澳大利亚胰腺癌基因组计划）PACA-AU队列的测序数据来表征MGMT沉默的PAC。对基因组、转录组、甲基化和临床数据进行了研究，并使用来自癌症细胞系百科全书（CCLE）项目的甲基化、转录组和药物敏感性数据以及在米兰国家肿瘤研究所（INT）对MGMT状态进行分析的PAC患者真实队列中进行了计算机模拟验证。
基于人类甲基化450k数据，在约6%的PAC病例中发现了MGMT沉默，且在非导管组织学肿瘤中富集，总体生存有延长趋势。MGMT沉默的肿瘤与KRAS突变频率较低相关，并表现出免疫排斥特征。在INT队列中，约7%的病例证实存在MGMT沉默，且在KRAS野生型肿瘤中普遍存在，具有良好的预后影响。计算机模拟分析表明，MGMT沉默的PAC细胞系对烷化剂和DNA损伤剂更敏感。
MGMT沉默发生在一小部分PAC中，且在KRAS野生型病例中富集，具有良好的预后影响。我们的研究结果为探索在MGMT沉默的PAC中联合使用烷化剂和DNA损伤剂提供了理论依据。
