Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation

Abstract

Pediatric-type follicular lymphoma (PTFL) is a B-cell lymphoma with distinctive clinicopathological features. Recently, recurrent genetic alterations of potential importance for its pathogenesis that disrupt pathways associated with the germinal center reaction (<i>TNFRSF14</i>, <i>IRF8</i>), immune escape (<i>TNFRSF14</i>), and anti-apoptosis (<i>MAP2K1</i>) have been described. In an attempt to shed more light onto the pathogenesis of PTFL, an integrative analysis of these mutations was undertaken in a large cohort of 43 cases previously characterized by targeted next-generation sequencing and copy number array. Mutations in <i>MAP2K1</i> were found in 49% (20/41) of the cases, second in frequency to <i>TNFRSF14</i> alterations (22/41; 54%), and all together were present in 81% of the cases. Immunohistochemical analysis of the <i>MAP2K1</i> downstream target extracellular signal-regulated kinase demonstrated its phosphorylation in the evaluable cases and revealed a good correlation with the allelic frequency of the <i>MAP2K1</i> mutation. The <i>IRF8</i> p.K66R mutation was present in 15% (6/39) of the cases and was concomitant with <i>TNFRSF14</i> mutations in 4 cases. This hot spot seems to be highly characteristic for PTFL. In conclusion, <i>TNFRSF14</i> and <i>MAP2K1</i> mutations are the most frequent genetic alterations found in PTFL and occur independently in most cases, suggesting that both mutations might play an important role in PTFL lymphomagenesis.