Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer
Δημιουργός/Συγγραφέας:	Vlachavas, Efstathios-Iason [EL] Βουτετάκης, Κωνσταντίνος[EN] Voutetakis, Konstantinos [EL] Κοσμίδου, Παρασκευή[EN] Kosmidou, Paraskevi Tsikalakis, Spyridon Roditis, Spyridon Pateas, Konstantinos Kim, Ryangguk Pagel, Kymberleigh Wolf, Stephan Warsow, Gregor Dimitrakopoulou-Strauss, Antonia Zografos, Georgios N [EL] Πίντζας, Αλέξανδρος[EN] Pintzas, Alexander Betge, Johannes [EL] Παπαδόδημα, Όλγα[EN] Papadodima, Olga Wiemann, Stefan
Ημερομηνία:	2025-01-28
Γλώσσα:	Αγγλικά
ISSN:	1574-7891 1878-0261
DOI:	10.1002/1878-0261.13814
Άλλο:	39876058
Περίληψη:	Colorectal cancer (CRC) patients with microsatellite-stable (MSS) tumors are mostly treated with chemotherapy. Clinical benefits of targeted therapies depend on mutational states and tumor location. Many tumors carry mutations in KRAS proto-oncogene, GTPase (KRAS) or B-Raf proto-oncogene, serine/threonine kinase (BRAF), rendering them more resistant to therapies. We performed whole-exome sequencing and RNA-Sequencing of 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized CRC patients based on their microsatellite instability (MSI) status, single-nucleotide variations (SNVs)/copy number alterations (CNAs), and pathway/transcription factor activities at the individual patient level. Variants were classified using a computational score for integrative cancer variant annotation and prioritization. Complementing this with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be more strongly activated in MSS patients, whereas Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) molecular cascades were activated specifically in MSI tumors. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified Runt-related transcription factors (RUNX transcription factors) as putative biomarkers in CRC, given their role in the regulation of pathways involved in tumor progression and immune evasion. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impact that KRAS mutations have on immunogenicity, particularly in the MSS patient subgroup, with implications for diagnosis and treatment.
Τίτλος πηγής δημοσίευσης:	Molecular oncology
Θεματική Κατηγορία:	[EL] Βιοπληροφορική[EN] Bioinformatics [EL] Νεοπλάσματα. Όγκοι. Ογκολογία (περ. Καρκίνος, κακινογόνες ουσίες)[EN] Neoplasms. Tumors. Oncology (Incl.cancer, carcinogens) [EL] Μοριακή Βιολογία[EN] Molecular Biology [EL] Βιοχημεία[EN] Biochemistry
Λέξεις-Κλειδιά:	CRC MSI status RAS/RAF SNVs/CNAs WES/RNA‐sequencing pathway/TF activity
Κάτοχος πνευματικών δικαιωμάτων:	© 2025 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1002/1878-0261.13814
Σημειώσεις:	The authors thank the teams of the DKFZ High-Throughput Sequencing and the OMICS IT Core Facilities for per-forming excellent services. We thank Julio Saez-Rodriguez, Aurelien Dugourd, and Marcos Dıaz-Gay for support concerning the implementation of pathway/TF activities and COSMIC signature analysis, respectively. This study was supported by the Helmholtz European Partnering Program ‘Athens Comprehensive Cancer Center (ACCC)’ in the course of a strategic collabora-tion between the National Hellenic Research Founda-tion (NHRF), the G. Gennimatas Hospital, the Medical School of the University of Athens, and the German Cancer Research Center (DKFZ). Open Access funding enabled and organized by Projekt DEAL.
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο