A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.

TitleA DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin.
Publication TypeJournal Article
Year of Publication2021
AuthorsMoura, DS, Peña-Chilet, M, Varela, JAntonio Co, Alvarez-Alegret, R, Agra-Pujol, C, Izquierdo, F, Ramos, R, Ortega-Medina, L, Martin-Davila, F, Castilla-Ramirez, C, Hernandez-Leon, CNieves, Romagosa, C, Salgado, MAngeles Va, Lavernia, J, Bagué, S, Mayodormo-Aranda, E, Vicioso, L, Barceló, JEmilio Her, Rubio-Casadevall, J, de Juan, A, Fiaño-Valverde, MConcepcion, Hindi, N, Lopez-Alvarez, M, Lacerenza, S, Dopazo, J, Gutierrez, A, Alvarez, R, Valverde, C, Martinez-Trufero, J, Martin-Broto, J
JournalMol Oncol
Date Published2021 May 13
ISSN1878-0261
Abstract

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.

DOI10.1002/1878-0261.12996
Alternate JournalMol Oncol
PubMed ID33983674
Grant List / / Spanish Group for Research on Sarcoma /
/ / PharmaMar /
CD20/00155 / / National Institute of Health Carlos III (ISCIII) /