Fundamental prognostic difference of ATM gene mutation and deletion in newly diagnosed mantle cell lymphoma.

Background: Previous studies have suggested that, after acquisition of t(11;14), mantle cell lymphoma (MCL) pathogenesis may proceed via several different genetic second hits, which may shape different mutational profiles of clinically manifest lymphoma. The most prevalent second hit in MCL includes ATM aberrations, accounting for about half of patients with newly diagnosed MCL. As ATM and TP53 mutations tend to be exclusive in MCL, we retrospectively analyzed the prognostic role of ATM deletions and/or mutations in patients with newly diagnosed MCL, both in the entire cohort and in a subcohort of patients with wild-type TP53.

Methods: To investigate deletions and mutations of ATM and TP53 in newly diagnosed MCL, we used fluorescence in situ hybridization and next-generation sequencing. To assess relationships between variables, non-parametric (Spearman) and chi-square tests were used. The Kruskal-Wallis test was used to analyze differences in continuous variables between two groups of patients. For survival analyses, the standard Kaplan-Meier estimator and log-rank test were employed. Univariate and multivariate Cox proportional hazard models were used to examine the prognostic value of various factors on patient survival.

Results: We analyzed 187 patients with MCL (a median follow-up of 3.6 years). Eighty-one (43%) and 75 (40%) patients had ATM and TP53 aberrations, respectively. Of note, three (9%) patients with mutated ATM harbored a germline mutation. Patients with TP53 aberration had shorter survival rates. Although ATM deletion did not correlate with progression-free survival (PFS) in the entire cohort, it was associated with shorter PFS (hazard ratio 2.25, p = 0.01) in patients with wild-type TP53. A higher frequency of ATM deletion correlated with shorter PFS. Patients with ATM mutation (and wild-type TP53) had a trend toward better PFS (albeit not statistically significant). Moreover, patients with a higher variant allele frequency of ATM mutation tended to have longer PFS.

Conclusions: ATM deletion is an important predictor of prognosis in MCL patients and should be routinely examined, especially in those with wild-type TP53. In contrast, an isolated ATM mutation may predict a better prognosis in the context of standard immunochemotherapy.