1. Molecular Characterization and Clinical Relevance of MGMT-Silenced Pancreatic Cancer.
- Author
-
Nichetti F, Silvestri M, Agnelli L, Franza A, Pircher C, Rota S, Ambrosini P, Fotia G, Hüllein J, Randon G, Lajer P, Perrone F, Tamborini E, Leoncini G, Coppa J, Busset MDD, Pusceddu S, Milione M, Morano F, Pietrantonio F, Pruneri G, Mazzaferro V, Lipka DB, Köhler BC, Hübschmann D, Fröhling S, de Braud F, and Niger M
- Subjects
- Humans, Male, Female, Aged, Middle Aged, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Prognosis, Biomarkers, Tumor genetics, Clinical Relevance, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms mortality, Tumor Suppressor Proteins genetics, DNA Modification Methylases genetics, DNA Modification Methylases metabolism, DNA Repair Enzymes genetics, DNA Methylation, Gene Silencing
- 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., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2024
- Full Text
- View/download PDF