PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system
| Autor: | Zimmer, Kai, Kocher, Florian, Untergasser, Gerold, Kircher, Brigitte, Amann, Arno, Baca, Yasmine, Macarulla, Teresa, Tabernero, Josep |
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| Přispěvatelé: | Institut Català de la Salut, [Zimmer K, Kocher F, Amann A] Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria. [Untergasser G, Kircher B] Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria. Tyrolean Cancer Research Institute, Innsbruck, Austria. [Baca Y] Caris Life Sciences, Phoenix, AZ, USA. [Macarulla T, Tabernero J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. IOB-Quiron, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Cromatina
Genetic Phenomena::Genetic Structures::Chromosome Structures::Chromatin [PHENOMENA AND PROCESSES] Therapeutics::Drug Therapy::Molecular Targeted Therapy [ANALYTICAL DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT] Anomalies cromosòmiques Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Biliary Tract Neoplasms::Bile Duct Neoplasms [DISEASES] Conductes biliars - Càncer - Tractament Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES] neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias del tracto biliar::neoplasias de los conductos biliares [ENFERMEDADES] fenómenos genéticos::estructuras genéticas::estructuras cromosómicas::cromatina [FENÓMENOS Y PROCESOS] terapéutica::farmacoterapia::terapia molecular selectiva [TÉCNICAS Y EQUIPOS ANALÍTICOS DIAGNÓSTICOS Y TERAPÉUTICOS] fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS] |
| Zdroj: | Scientia |
| Popis: | Cancer genomics; Oncology Genómica del cáncer; Oncología Genòmica del càncer; Oncologia Polybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs. |
| Databáze: | OpenAIRE |
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