A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin
Por:
Moura, DS, Pena-Chilet, M, Varela, JAC, Alvarez-Alegret, R, Agra-Pujol, C, Izquierdo, F, Ramos, R, Ortega-Medina, L, Martin-Davila, F, Castilla-Ramirez, C, Hernandez-Leon, CN, Romagosa, C, Salgado, MAV, Lavernia, J, Bague, S, Mayodormo-Aranda, E, Vicioso, L, Barcelo, JEH, Rubio-Casadevall, J, de Juan, A, Fiano-Valverde, MC, Hindi, N, Lopez-Alvarez, M, Lacerenza, S, Dopazo, J, Gutierrez, A, Alvarez, R, Valverde, C, Martinez-Trufero, J, Martin-Broto, J
Publicada:
1 dic 2021
Ahead of Print:
1 jun 2021
Resumen:
Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.
Filiaciones:
Moura, DS:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Pena-Chilet, M:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Hosp Virgen del Rocio, Fdn Progreso & Salud FPS, CDCA, Clin Bioinformat Area, Seville, Spain
Hosp Virgen del Rocio, Ctr Invest Biomed Red Enfermedades Raras CIBERER, FPS, Bioinformat Rare Dis BiER, Seville, Spain
Varela, JAC:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Alvarez-Alegret, R:
Miguel Servet Univ Hosp, Pathol Dept, Zaragoza, Spain
Agra-Pujol, C:
Gregorio Maranon Univ Hosp, Pathol Dept, Madrid, Spain
Izquierdo, F:
Complejo Asistencial Univ Leon, Pathol Anat Serv, Leon, Spain
Ramos, R:
Son Espases Univ Hosp, Pathol Dept, Mallorca, Spain
Ortega-Medina, L:
Hosp Clin San Carlos, Pathol Dept, Madrid, Spain
Martin-Davila, F:
Ciudad Real Gen Hosp, Pathol Dept, Ciudad Real, Spain
Castilla-Ramirez, C:
Univ Hosp Virgen del Rocio, Pathol Dept, Seville, Spain
Hernandez-Leon, CN:
Canarias Univ Hosp, Pathol Dept, Santa Cruz De Tenerife, Spain
Romagosa, C:
Vall dHebron Univ Hosp, Pathol Dept, Barcelona, Spain
Salgado, MAV:
Ramon y Cajal Univ Hosp, Med Oncol Dept, Madrid, Spain
Lavernia, J:
Inst Valenciano Oncol, Med Oncol Dept, Valencia, Spain
Bague, S:
Hosp Santa Creu & Sant Pau, Pathol Serv, Barcelona, Spain
Mayodormo-Aranda, E:
Hosp Univ & Politecn La Fe, Pathol Dept, Valencia, Spain
Vicioso, L:
Virgen de la Victoria Univ Hosp, Pathol Dept, Malaga, Spain
Barcelo, JEH:
Virgen de la Arrixaca Univ Hosp, Pathol Dept, Murcia, Spain
Rubio-Casadevall, J:
Hosp Josep Trueta, Catalan Inst Oncol, Med Oncol Dept, Girona, Spain
de Juan, A:
Marques de Valdecilla Univ Hosp, Med Oncol Dept, Santander, Spain
Fiano-Valverde, MC:
Alvaro Cunqueiro Hosp, Dept Histopathol, Univ Hosp Complex Vigo, Vigo, Spain
Hindi, N:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Univ Hosp Fdn Jimenez Diaz, Med Oncol Dept, Madrid, Spain
Univ Hosp Gen Villalba, Madrid, Spain
Inst Invest Sanitaria Fdn Jimenez Diaz IIS FJD, Madrid, Spain
Lopez-Alvarez, M:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Lacerenza, S:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Dopazo, J:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Hosp Virgen del Rocio, Fdn Progreso & Salud FPS, CDCA, Clin Bioinformat Area, Seville, Spain
Hosp Virgen del Rocio, Ctr Invest Biomed Red Enfermedades Raras CIBERER, FPS, Bioinformat Rare Dis BiER, Seville, Spain
Hosp Virgen del Rocio, FPS, INB ELIXIR Es, Seville, Spain
Gutierrez, A:
Son Espases Univ Hosp, Hematol Dept, Mallorca, Spain
Alvarez, R:
Gregorio Maranon Univ Hosp, Med Oncol Dept, Madrid, Spain
Valverde, C:
Vall dHebron Univ Hosp, Med Oncol Dept, Barcelona, Spain
Martinez-Trufero, J:
Miguel Servet Univ Hosp, Med Oncol Dept, Zaragoza, Spain
Martin-Broto, J:
Univ Seville, Inst Biomed Seville IBIS, CSIC, HUVR, Seville, Spain
Univ Hosp Fdn Jimenez Diaz, Med Oncol Dept, Madrid, Spain
Univ Hosp Gen Villalba, Madrid, Spain
Inst Invest Sanitaria Fdn Jimenez Diaz IIS FJD, Madrid, Spain
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