Molecular Characterization and Clinical Relevance of MGMT-Silenced Pancreatic Cancer.

Autor:	Nichetti F; 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., Silvestri M; Department of Diagnostic Innovation, Second Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Agnelli L; Department of Diagnostic Innovation, Second Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Franza A; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Pircher C; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Rota S; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Ambrosini P; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Fotia G; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Hüllein J; Computational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Randon G; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Lajer P; Division of Translational Medical Oncology, Section of Translational Cancer Epigenomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany., Perrone F; Department of Diagnostic Innovation, Second Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Tamborini E; Department of Diagnostic Innovation, Second Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Leoncini G; Department of Pathology and Laboratory Medicine, First Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Coppa J; Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Busset MDD; Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Pusceddu S; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Milione M; Department of Pathology and Laboratory Medicine, First Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Morano F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Pietrantonio F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy., Pruneri G; Department of Diagnostic Innovation, Second Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Mazzaferro V; Hepato-Pancreato-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Lipka DB; Division of Translational Medical Oncology, Section of Translational Cancer Epigenomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany., Köhler BC; Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Hübschmann D; Computational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.; Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany., Fröhling S; Division of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., de Braud F; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.; Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy., Niger M; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Jazyk:	angličtina
Zdroj:	Cancer medicine [Cancer Med] 2024 Dec; Vol. 13 (23), pp. e70393.
DOI:	10.1002/cam4.70393
Abstrakt:	Background: 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. Experimental Design: 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). Results: 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. Conclusions: 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. (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
Databáze:	MEDLINE
Externí odkaz: