A Study of the Mutational Landscape of Pediatric-type Follicular Lymphoma and Pediatric Nodal Marginal Zone Lymphoma

Overview

Journal Mod Pathol

Specialty Pathology

Date 2016 Jun 25

PMID 27338637

Citations 21

Authors

Michael G Ozawa

Aparna Bhaduri

Karen M Chisholm

Steven A Baker

Lisa Ma

James L Zehnder

Sandra Luna-Fineman

Michael P Link

Jason D Merker

Daniel A Arber

Robert S Ohgami

Affiliations

Soon will be listed here.

Abstract

Pediatric-type follicular lymphoma and pediatric marginal zone lymphoma are two of the rarest B-cell lymphomas. These lymphomas occur predominantly in the pediatric population and show features distinct from their more common counterparts in adults: adult-type follicular lymphoma and adult-type nodal marginal zone lymphoma. Here we report a detailed whole-exome deep sequencing analysis of a cohort of pediatric-type follicular lymphomas and pediatric marginal zone lymphomas. This analysis revealed a recurrent somatic variant encoding p.Lys66Arg in the transcription factor interferon regulatory factor 8 (IRF8) in 3 of 6 cases (50%) of pediatric-type follicular lymphoma. This specific point mutation was not detected in pediatric marginal zone lymphoma or in adult-type follicular lymphoma. Additional somatic point mutations in pediatric-type follicular lymphoma were observed in genes involved in transcription, intracellular signaling, and cell proliferation. In pediatric marginal zone lymphoma, no recurrent mutation was identified; however, somatic point mutations were observed in genes involved in cellular adhesion, cytokine regulatory elements, and cellular proliferation. A somatic variant in AMOTL1, a recurrently mutated gene in splenic marginal zone lymphoma, was also identified in a case of pediatric marginal zone lymphoma. The overall non-synonymous mutational burden was low in both pediatric-type follicular lymphoma and pediatric marginal zone lymphoma (4.6 mutations per exome). Altogether, these findings support a distinctive genetic basis for pediatric-type follicular lymphoma and pediatric marginal zone lymphoma when compared with adult subtypes and to one another. Moreover, identification of a recurrent point mutation in IRF8 provides insight into a potential driver mutation in the pathogenesis of pediatric-type follicular lymphoma with implications for novel diagnostic or therapeutic strategies.

Citing Articles

A rare case of primary testicular follicular lymphoma in a pediatric patient.

Nguyen A, King R, Viswanatha D, Peterson J, Rahimi N, Artymiuk C J Hematop. 2025; 18(1):3.

PMID: 39862366 DOI: 10.1007/s12308-025-00619-9.

Adult-Onset Pediatric-Type Follicular Lymphoma of the Parotid Gland.

Albaldawy M, Ebaied T, Bin Harmal Al Shamsi H, Nadaf A, Faruk Abbu R Cureus. 2025; 16(12):e76161.

PMID: 39840177 PMC: 11747981. DOI: 10.7759/cureus.76161.

Pediatric lymphomas: overview and diagnostic challenges.

Choi J, Quintanilla-Martinez L Virchows Arch. 2024; 486(1):81-100.

PMID: 39707053 PMC: 11782321. DOI: 10.1007/s00428-024-03980-9.

Genomic landscape of testicular follicular lymphoma is characterized by frequent 1p36/TNFRSF14 alterations.

Zhang W, Perry A, Hamnvag H, Kitahara S, Kitahara S, Ondrejka S Blood Adv. 2024; 9(4):814-817.

PMID: 39602674 PMC: 11869950. DOI: 10.1182/bloodadvances.2024014002.

Pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma: additional evidence to support they are a single disease with variation in the histologic spectrum.

Li H, Jiang X, Xue T, Xin B, Chen L, Li G Virchows Arch. 2024; 485(5):889-900.

PMID: 39379519 PMC: 11564197. DOI: 10.1007/s00428-024-03941-2.

References

Clipson A, Wang M, de Leval L, Ashton-Key M, Wotherspoon A, Vassiliou G . KLF2 mutation is the most frequent somatic change in splenic marginal zone lymphoma and identifies a subset with distinct genotype. Leukemia. 2014; 29(5):1177-85. DOI: 10.1038/leu.2014.330. View

Karnik T, Ozawa M, Lefterova M, Luna-Fineman S, Alvarez E, Link M . The utility of IgM, CD21, HGAL and LMO2 in the diagnosis of pediatric follicular lymphoma. Hum Pathol. 2015; 46(4):629-33. DOI: 10.1016/j.humpath.2014.12.016. View

Newman A, Bratman S, Stehr H, Lee L, Liu C, Diehn M . FACTERA: a practical method for the discovery of genomic rearrangements at breakpoint resolution. Bioinformatics. 2014; 30(23):3390-3. PMC: 4296148. DOI: 10.1093/bioinformatics/btu549. View

Xu H, Zhu J, Smith S, Foldi J, Zhao B, Chung A . Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat Immunol. 2012; 13(7):642-50. PMC: 3513378. DOI: 10.1038/ni.2304. View

Xu H, Chaudhri V, Wu Z, Biliouris K, Dienger-Stambaugh K, Rochman Y . Regulation of bifurcating B cell trajectories by mutual antagonism between transcription factors IRF4 and IRF8. Nat Immunol. 2015; 16(12):1274-81. DOI: 10.1038/ni.3287. View

Taddesse-Heath L, Pittaluga S, Sorbara L, Bussey M, Raffeld M, Jaffe E . Marginal zone B-cell lymphoma in children and young adults. Am J Surg Pathol. 2003; 27(4):522-31. PMC: 6324530. DOI: 10.1097/00000478-200304000-00014. View

Supek F, Minana B, Valcarcel J, Gabaldon T, Lehner B . Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014; 156(6):1324-1335. DOI: 10.1016/j.cell.2014.01.051. View

Weinhold N, Jacobsen A, Schultz N, Sander C, Lee W . Genome-wide analysis of noncoding regulatory mutations in cancer. Nat Genet. 2014; 46(11):1160-5. PMC: 4217527. DOI: 10.1038/ng.3101. View

Banerjee S, Lu J, Cai Q, Saha A, Jha H, Dzeng R . The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8. PLoS Pathog. 2013; 9(5):e1003314. PMC: 3642079. DOI: 10.1371/journal.ppat.1003314. View

10.

Swerdlow S, Campo E, Pileri S, Lee Harris N, Stein H, Siebert R . The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20):2375-90. PMC: 4874220. DOI: 10.1182/blood-2016-01-643569. View

11.

Zhang J, Dominguez-Sola D, Hussein S, Lee J, Holmes A, Bansal M . Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis. Nat Med. 2015; 21(10):1190-8. PMC: 5145002. DOI: 10.1038/nm.3940. View

12.

Becker A, Michael D, Satpathy A, Sciammas R, Singh H, Bhattacharya D . IRF-8 extinguishes neutrophil production and promotes dendritic cell lineage commitment in both myeloid and lymphoid mouse progenitors. Blood. 2012; 119(9):2003-12. PMC: 3311244. DOI: 10.1182/blood-2011-06-364976. View

13.

Ribeiro R, Pui C, MURPHY S, Shuster J, Hvizdala E, Falletta J . Childhood malignant non-Hodgkin lymphomas of uncommon histology. Leukemia. 1992; 6(8):761-5. View

14.

Loeffler M, Kreuz M, Haake A, Hasenclever D, Trautmann H, Arnold C . Genomic and epigenomic co-evolution in follicular lymphomas. Leukemia. 2014; 29(2):456-63. DOI: 10.1038/leu.2014.209. View

15.

Escalante C, Brass A, Pongubala J, Shatova E, Shen L, Singh H . Crystal structure of PU.1/IRF-4/DNA ternary complex. Mol Cell. 2002; 10(5):1097-105. DOI: 10.1016/s1097-2765(02)00703-7. View

16.

Parry M, Rose-Zerilli M, Gibson J, Ennis S, Walewska R, Forster J . Whole exome sequencing identifies novel recurrently mutated genes in patients with splenic marginal zone lymphoma. PLoS One. 2013; 8(12):e83244. PMC: 3862727. DOI: 10.1371/journal.pone.0083244. View

17.

Martinez N, Almaraz C, Vaque J, Varela I, Derdak S, Beltran S . Whole-exome sequencing in splenic marginal zone lymphoma reveals mutations in genes involved in marginal zone differentiation. Leukemia. 2013; 28(6):1334-40. DOI: 10.1038/leu.2013.365. View

18.

Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T . SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014; 42(Web Server issue):W252-8. PMC: 4086089. DOI: 10.1093/nar/gku340. View

19.

Martin-Guerrero I, Salaverria I, Burkhardt B, Szczepanowski M, Baudis M, Bens S . Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas. Haematologica. 2013; 98(8):1237-41. PMC: 3729904. DOI: 10.3324/haematol.2012.073916. View

20.

Morin R, Johnson N, Severson T, Mungall A, An J, Goya R . Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010; 42(2):181-5. PMC: 2850970. DOI: 10.1038/ng.518. View