Tumors bearing homologous recombination deficiency are extremely sensitive to DNA double strand breaks induced by several chemotherapeutic agents. ATM gene, encoding a protein involved in DNA damage response, is frequently mutated in colorectal cancer (CRC), but its potential role as predictive and prognostic biomarker has not been fully investigated. We carried out a multicenter effort aimed at defining the prognostic impact of ATM mutational status in metastatic CRC (mCRC) patients. Mutational profiles were obtained by means of next-generation sequencing. Overall, 35 out of 227 samples (15%) carried an ATM mutation. At a median follow-up of 56.6 months, patients with ATM mutated tumors showed a significantly longer median overall survival (OS) versus ATM wild-type ones (64.9 vs 34.8 months; HR, 0.50; 95% CI, 0.29-0.85; P = 0.01). In the multivariable model, ATM mutations confirmed the association with longer OS (HR, 0.57; 95% CI, 0.33-0.98; P = 0.04). The prognostic impact of ATM mutations was independent from TP53 mutational status and primary tumor location. High heterogeneity score for ATM mutations, possibly reflecting the loss of wild-type allele, was associated with excellent prognosis. In conclusion, we showed that ATM mutations are independently associated with longer OS in patients with mCRC.
|Autori:||Randon, Giovanni; Fucà, Giovanni; Rossini, Daniele; Raimondi, Alessandra; Pagani, Filippo; Perrone, Federica; Tamborini, Elena; Busico, Adele; Peverelli, Giorgia; Morano, Federica; Niger, Monica; Antista, Maria; Corallo, Salvatore; Saggio, Serena; Borelli, Beatrice; Zucchelli, Gemma; Milione, Massimo; Pruneri, Giancarlo; Di Bartolomeo, Maria; Falcone, Alfredo; de Braud, Filippo; Cremolini, Chiara; Pietrantonio, Filippo|
|Titolo:||Prognostic impact of ATM mutations in patients with metastatic colorectal cancer|
|Anno del prodotto:||2019|
|Digital Object Identifier (DOI):||10.1038/s41598-019-39525-3|
|Appare nelle tipologie:||1.1 Articolo in rivista|