Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations.
Pediatric-type nodal follicular lymphoma (PTNFL) is a variant of follicular lymphoma (FL) characterized by limited-stage presentation and invariably benign behavior despite often high-grade histological appearance. It is important to distinguish PTNFL from typical FL in order to avoid unnecessary treatment; however, this distinction relies solely on clinical and pathological criteria, which may be variably applied. To define the genetic landscape of PTNFL, we performed copy number analysis and exome and/or targeted sequencing of 26 PTNFLs (16 pediatric and 10 adult). The most commonly mutated gene in PTNFL was MAP2K1, encoding MEK1, with a mutation frequency of 43%. All MAP2K1 mutations were activating missense mutations localized to exons 2 and 3, which encode negative regulatory and catalytic domains, respectively. Missense mutations in MAPK1 (2/22) and RRAS (1/22) were identified in cases that lacked MAP2K1 mutations. The second most commonly mutated gene in PTNFL was TNFRSF14, with a mutation frequency of 29%, similar to that seen in limited-stage typical FL (P = .35). PTNFL was otherwise genomically bland and specifically lacked recurrent mutations in epigenetic modifiers (eg, CREBBP, KMT2D). Copy number aberrations affected a mean of only 0.5% of PTNFL genomes, compared with 10% of limited-stage typical FL genomes (P < .02). Importantly, the mutational profiles of PTNFLs in children and adults were highly similar. Together, these findings define PTNFL as a biologically and clinically distinct indolent lymphoma of children and adults characterized by a high prevalence of MAPK pathway mutations and a near absence of mutations in epigenetic modifiers.
Department of Pathology, Massachusetts General Hospital, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Abner
A
Louissaint
Department of Pathology and Laboratory Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL;
Kristian T
KT
Schafernak
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York-Presbyterian Hospital, New York, NY;
Julia T
JT
Geyer
Department of Pathology, Boston Children's Hospital, Boston, MA;
Alexandra E
AE
Kovach
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
Mahmoud
M
Ghandi
Department of Pathology, Stanford University School of Medicine, Stanford, CA;
Dita
D
Gratzinger
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA;
Christine G
CG
Roth
ARUP Institute for Clinical and Experimental Pathology, Department of Pathology, University of Utah, Salt Lake City, UT;
Christian N
CN
Paxton
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
Sunhee
S
Kim
Department of Pathology, Brigham & Women's Hospital, Boston, MA;
Chungdak
C
Namgyal
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada;
Ryan
R
Morin
Department of Pathology, Brigham & Women's Hospital, Boston, MA;
Elizabeth A
EA
Morgan
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
Donna S
DS
Neuberg
ARUP Laboratories, Department of Pathology, University of Utah, Salt Lake City, UT; and.
Sarah T
ST
South
Department of Pathology, Boston Children's Hospital, Boston, MA;
Marian H
MH
Harris
Department of Pathology, Massachusetts General Hospital, Boston, MA;
Robert P
RP
Hasserjian
Department of Medicine, Massachusetts General Hospital, Boston, MA.
Ephraim P
EP
Hochberg
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
Levi A
LA
Garraway
Department of Pathology, Massachusetts General Hospital, Boston, MA;
Nancy Lee
NL
Harris
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA;
David M
DM
Weinstock
D000293:Adolescent; D000367:Age Factors; D048430:Cell Shape; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D008224:Lymphoma, Follicular / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*