Prognostic impact of ATM mutations in patients with metastatic colorectal cancer

Giovanni Randon, Giovanni Fucà, Daniele Rossini, Alessandra Raimondi, Filippo Pagani, Federica Perrone, Elena Tamborini, Adele Busico, Giorgia Peverelli, Federica Morano, Monica Niger, Maria Antista, Salvatore Corallo, Serena Saggio, Beatrice Borelli, Gemma Zucchelli, Massimo Milione, Giancarlo Pruneri, Maria Di Bartolomeo, Alfredo FalconeFilippo de Braud, Chiara Cremolini, Filippo Pietrantonio

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2858
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

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    Randon, G., Fucà, G., Rossini, D., Raimondi, A., Pagani, F., Perrone, F., Tamborini, E., Busico, A., Peverelli, G., Morano, F., Niger, M., Antista, M., Corallo, S., Saggio, S., Borelli, B., Zucchelli, G., Milione, M., Pruneri, G., Di Bartolomeo, M., ... Pietrantonio, F. (2019). Prognostic impact of ATM mutations in patients with metastatic colorectal cancer. Scientific Reports, 9(1), [2858]. https://doi.org/10.1038/s41598-019-39525-3