Over 30% of patients with splenic marginal zone lymphoma express the same immunoglobulin heavy variable gene: ontogenetic implications.
We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.
Democritus University of Thrace, Alexandroupolis, Greece.
V
V
Bikos
N
N
Darzentas
A
A
Hadzidimitriou
Z
Z
Davis
S
S
Hockley
A
A
Traverse-Glehen
P
P
Algara
A
A
Santoro
D
D
Gonzalez
M
M
Mollejo
A
A
Dagklis
F
F
Gangemi
D S
DS
Bosler
G
G
Bourikas
A
A
Anagnostopoulos
A
A
Tsaftaris
E
E
Iannitto
M
M
Ponzoni
P
P
Felman
F
F
Berger
C
C
Belessi
P
P
Ghia
T
T
Papadaki
A
A
Dogan
M
M
Degano
E
E
Matutes
M A
MA
Piris
D
D
Oscier
K
K
Stamatopoulos
D015331:Cohort Studies; D022801:Complementarity Determining Regions / Q000235:genetics*; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D011379:Prognosis; D013160:Splenic Neoplasms / Q000235:genetics*
D022801:Complementarity Determining Regions; D007135:Immunoglobulin Variable Region