Prognostic impact of ATM mutations in patients with metastatic colorectal cancer

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.

Enhancing the Landscape of Colorectal Cancer Using Targeted Deep Sequencing

“…The TCGA and MSKCC dataset reported that ATM mutations were detected in 14% and 7% of CRC patients, respectively. Randon et al found that ATM mutations are independently associated with longer OS in patients with metastatic CRC [26]. However, we revealed that ATM mutation is linked to poorer OS in patients with CRC.…”

“…In addition, no differences were observed in the OS according to ATM mutation status in both TCGA and MSKCC cohorts. The discrepancy among studies might be due to the different prognostic role of ATM according to the disease stage and the confounding factors from the heterogeneity of available treatment strategies used for metastatic disease [26].…”

Durable Near-Complete Response to Olaparib Plus Temozolomide and Radiation in a Patient With ATM-Mutated Glioblastoma and MSH6-Deficient Lynch Syndrome

“… 37 They are associated with increased platinum sensitivity and superior survival. 37 , 38 Tumors with loss-of-function ATM mutations have increased radiosensitivity. 39 ATM suppression in the setting of p53 deficiency sensitizes tumors to DNA-damaging chemotherapy and radiotherapy, whereas ATM suppression with intact p53 leads to a worse response.…”

Genomic Profiling of Stage II Colorectal Cancer Identifies Candidate Genes Associated with Recurrence-Free Survival, Tumor Location, and Differentiation Grade

“…Reduced protein expression of ATM has been suggested as a biomarker of poor RFS in CRC stage II/III [29], supporting the potential importance of ATM, C11ORF65 as a prognostic marker noticed here. In the context of metastatic disease reduced ATM protein expression, as well as genetic variants of ATM, have been related with increased chemosensitivity to oxaliplatin-based therapy and overall survival [30,31]. However, the concordance between protein loss and presence of genetic variation, when described, was relatively weak [30].…”