Pediatric follicular lymphomas involve interactions in MAPK and G-protein protein receptor signaling pathways, according to results of a new study. This study, published online in Haematologica, identified a number of novel mutations and signaling pathways associated with pediatric follicular lymphomas.

Classic follicular lymphoma, an indolent B-cell lymphoma, is very rare in children, whereas pediatric-type nodal follicular lymphoma (PTNFL) and primary follicular lymphoma of the testis (PFLT) occur more frequently in this population compared with adults. While the molecular landscape of classic follicular lymphoma has been more thoroughly studied, comparatively little is known about the molecular features of the pediatric variants of follicular lymphoma.

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This study used whole-exome sequencing or Sanger sequencing to investigate the molecular characteristics of specimens collected from a series of patients with PTNFL and PFLT treated at pediatric cancer centers in Italy during the period between December 2002 and May 2017. In addition, a mutational network was created to investigate potential functional interactions between somatic alterations in tumors in order to provide insight into possible biological mechanisms and signaling pathways involved in PTNFL and PFLT. 

Whole-exome sequencing was performed for the 9 cases where primary tumor and matched peripheral blood specimens were available (7 PTNFL; 2 PFLT); TNFRSF14 exon 1 mutations were assessed by Sanger sequencing for the 12 cases (11 PTNFL; 1 PFLT) with only primary tumor specimens.   

The results of the study showed that 38% of cases, including 1 case of PFLT, were characterized by a mutation in TNFRSF14 exon 1. Of the identified main component targeted genes somatically mutated in pediatric follicular lymphomas, those that were mutated in 1 or more individuals included ARHGEF1, RHPN2, NSD1,CYP2A6, FCGBP, MUC16, PABPC1, TNFRSF14, MAP2K1, and IRF8, with mutations in the latter 3 genes previously associated with pediatric follicular lymphomas.

Mutations in MAP2K1 were associated with mitogen-activated protein kinase (MAPK) signaling; mutations in ARHGEF1 mutations in RHPN2 were associated withG-coupled protein receptor(GPCR) signaling; NSD1 mutations were associated with chromatin modifiers; and mutations in TNFRSF14 were associated with B-cell differentiation. Mutations in other genes associated with each of these domains were also identified in pediatric follicular lymphoma tumor specimens, with more than half of the main component targeted gene mutations associated with 2 “highly interlaced pathways”: MAPK and GPCR. 

The study authors also noted that identified mutations in genes encoding for chromatin modifying enzymes “confirm that epigenetic mechanisms can contribute to PTNFL pathogenesis.”

“Our analysis at network level considerably extended previous data on the mutational landscape of FL of the pediatric age, further indicating the signaling pathways of possible pathogenic relevance in these malignancies,” the authors wrote in conclusion. 

Reference

  1. Lovisa F, Binatti A, Coppe A, et al. A high definition picture of key genes and pathways mutated in pediatric follicular lymphoma [published online February 28, 2019]. Haematologica. doi: 10.3324/haematol.2018.211631