Genetic heterogeneity and prognostic impact of recurrent ANK2 and TP53 mutations in mantle cell lymphoma: a multi-centre cohort study

Abstract

The molecular features of mantle cell lymphoma (MCL), including its increased incidence, and complex therapies have not been investigated in detail, particularly in East Asian populations. In this study, we performed targeted panel sequencing (TPS) and whole-exome sequencing (WES) to investigate the genetic alterations in Korean MCL patients. We obtained a total of 53 samples from MCL patients from five Korean university hospitals between 2009 and 2016. We identified the recurrently mutated genes such as SYNE1, ATM, KMT2D, CARD11, ANK2, KMT2C, and TP53, which included some known drivers of MCL. The mutational profiles of our cohort indicated genetic heterogeneity. The significantly enriched pathways were mainly involved in gene expression, cell cycle, and programmed cell death. Multivariate analysis revealed that ANK2 mutations impacted the unfavourable overall survival (hazard ratio [HR] 3.126; P = 0.032). Furthermore, TP53 mutations were related to worse progression-free survival (HR 7.813; P = 0.043). Among the recurrently mutated genes with more than 15.0% frequency, discrepancies were found in only 5 genes from 4 patients, suggesting comparability of the TPS to WES in practical laboratory settings. We provide the unbiased genetic landscape that might contribute to MCL pathogenesis and recurrent genes conferring unfavourable outcomes.

Figure 1

The mutational spectrum of 53 patients with mantle cell lymphoma. (a) Mutational spectrum with frequencies and clinical data. (b) Genes identified in the lymphoma panel only (left) or by whole-exome sequencing (WES) only (right).

Figure 2

Kaplan–Meier curves for overall survival and progression-free survival of patients with mantle cell lymphoma. Kaplan–Meier curves of (a) age classes for overall survival, (b) ANK2 mutation for overall survival, (c) KMT2C mutation for overall survival, (d) KMT2C mutation for progression-free survival, (e) MAP1B mutation for progression-free survival, and (f) TP53 mutation for progression-free survival. The presented P-values were calculated using the log-rank test.

Figure 3

Pathway analysis and amino acid changes resulting from the determined ANK2 and TP53 mutations. (a) Pathway analysis of mutational genes with a frequency of more than 15.0% in mantle cell lymphoma samples. (b) The location of amino acid changes resulting from ANK2 and (c) TP53 mutations.