Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features.
Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior.
Pathology and Hematology Departments, Hospital Clínic, University of Barcelona, Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Spain.
Alba
A
Navarro
Guillem
G
Clot
Cristina
C
Royo
Pedro
P
Jares
Anastasia
A
Hadzidimitriou
Andreas
A
Agathangelidis
Vasilis
V
Bikos
Nikos
N
Darzentas
Theodora
T
Papadaki
Itziar
I
Salaverria
Magda
M
Pinyol
Xavier
X
Puig
Jara
J
Palomero
Maria Carmela
MC
Vegliante
Virgina
V
Amador
Alejandra
A
Martinez-Trillos
Lenka
L
Stefancikova
Adrian
A
Wiestner
Wyndham
W
Wilson
Christiane
C
Pott
Maria Jose
MJ
Calasanz
Nicola
N
Trim
Wendy
W
Erber
Birgitta
B
Sander
German
G
Ott
Andreas
A
Rosenwald
Dolors
D
Colomer
Eva
E
Giné
Reiner
R
Siebert
Armando
A
Lopez-Guillermo
Kostas
K
Stamatopoulos
Sílvia
S
Beà
Elías
E
Campo
D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics*; D008297:Male; D009154:Mutation; D055751:SOXC Transcription Factors / Q000235:genetics*
D007143:Immunoglobulin Heavy Chains; C097473:SOX11 protein, human; D055751:SOXC Transcription Factors