Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer
ABSTRACT 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. Expe...
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2024-12-01
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| Online Access: | https://doi.org/10.1002/cam4.70393 |
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| author | Federico Nichetti Marco Silvestri Luca Agnelli Andrea Franza Chiara Pircher Simone Rota Paolo Ambrosini Giuseppe Fotia Jennifer Hüllein Giovanni Randon Panna Lajer Federica Perrone Elena Tamborini Giuseppe Leoncini Jorgelina Coppa Michele Droz Dit Busset Sara Pusceddu Massimo Milione Federica Morano Filippo Pietrantonio Giancarlo Pruneri Vincenzo Mazzaferro Daniel B. Lipka Bruno Christian Köhler Daniel Hübschmann Stefan Fröhling Filippo deBraud Monica Niger |
| author_facet | Federico Nichetti Marco Silvestri Luca Agnelli Andrea Franza Chiara Pircher Simone Rota Paolo Ambrosini Giuseppe Fotia Jennifer Hüllein Giovanni Randon Panna Lajer Federica Perrone Elena Tamborini Giuseppe Leoncini Jorgelina Coppa Michele Droz Dit Busset Sara Pusceddu Massimo Milione Federica Morano Filippo Pietrantonio Giancarlo Pruneri Vincenzo Mazzaferro Daniel B. Lipka Bruno Christian Köhler Daniel Hübschmann Stefan Fröhling Filippo deBraud Monica Niger |
| author_sort | Federico Nichetti |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-3eb55c237a314b16a53fe6575369b7af |
| institution | DOAJ |
| issn | 2045-7634 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-3eb55c237a314b16a53fe6575369b7af2025-08-20T02:50:26ZengWileyCancer Medicine2045-76342024-12-011323n/an/a10.1002/cam4.70393Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic CancerFederico Nichetti0Marco Silvestri1Luca Agnelli2Andrea Franza3Chiara Pircher4Simone Rota5Paolo Ambrosini6Giuseppe Fotia7Jennifer Hüllein8Giovanni Randon9Panna Lajer10Federica Perrone11Elena Tamborini12Giuseppe Leoncini13Jorgelina Coppa14Michele Droz Dit Busset15Sara Pusceddu16Massimo Milione17Federica Morano18Filippo Pietrantonio19Giancarlo Pruneri20Vincenzo Mazzaferro21Daniel B. Lipka22Bruno Christian Köhler23Daniel Hübschmann24Stefan Fröhling25Filippo deBraud26Monica Niger27Medical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyDepartment of Diagnostic Innovation, Second Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyDepartment of Diagnostic Innovation, Second Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyComputational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) Heidelberg GermanyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyDivision of Translational Medical Oncology, Section of Translational Cancer Epigenomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg GermanyDepartment of Diagnostic Innovation, Second Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyDepartment of Diagnostic Innovation, Second Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyDepartment of Pathology and Laboratory Medicine, First Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyHepato‐Pancreato‐Biliary Surgery and Liver Transplantation Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyHepato‐Pancreato‐Biliary Surgery and Liver Transplantation Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyDepartment of Pathology and Laboratory Medicine, First Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyDepartment of Diagnostic Innovation, Second Division of Pathology Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyHepato‐Pancreato‐Biliary Surgery and Liver Transplantation Fondazione IRCCS Istituto Nazionale dei Tumori Milan ItalyDivision of Translational Medical Oncology, Section of Translational Cancer Epigenomics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT) Heidelberg GermanyDivision of Translational Medical Oncology National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ) Heidelberg GermanyComputational Oncology, Molecular Precision Oncology Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ) Heidelberg GermanyDivision of Translational Medical Oncology National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ) Heidelberg GermanyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyMedical Oncology Department Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Milan ItalyABSTRACT 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.https://doi.org/10.1002/cam4.70393biomarkerKRAS wild typeMGMTmolecular profilingpancreatic cancertemozolomide |
| spellingShingle | Federico Nichetti Marco Silvestri Luca Agnelli Andrea Franza Chiara Pircher Simone Rota Paolo Ambrosini Giuseppe Fotia Jennifer Hüllein Giovanni Randon Panna Lajer Federica Perrone Elena Tamborini Giuseppe Leoncini Jorgelina Coppa Michele Droz Dit Busset Sara Pusceddu Massimo Milione Federica Morano Filippo Pietrantonio Giancarlo Pruneri Vincenzo Mazzaferro Daniel B. Lipka Bruno Christian Köhler Daniel Hübschmann Stefan Fröhling Filippo deBraud Monica Niger Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer Cancer Medicine biomarker KRAS wild type MGMT molecular profiling pancreatic cancer temozolomide |
| title | Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer |
| title_full | Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer |
| title_fullStr | Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer |
| title_full_unstemmed | Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer |
| title_short | Molecular Characterization and Clinical Relevance of MGMT‐Silenced Pancreatic Cancer |
| title_sort | molecular characterization and clinical relevance of mgmt silenced pancreatic cancer |
| topic | biomarker KRAS wild type MGMT molecular profiling pancreatic cancer temozolomide |
| url | https://doi.org/10.1002/cam4.70393 |
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