The mutator pathway is a feature of immunodeficiency-related lymphomas.
The mutator phenotype caused by defects in the mismatch repair system is observed in a subset of solid neoplasms characterized by widespread microsatellite instability-high (MSI-H). It is known to be very rare in non-Hodgkin lymphomas (NHL), whereas mutator NHL is the most frequent tumor subtype in mismatch repair-deficient mice. By screening a series of 603 human NHL with specific markers of the mutator phenotype, we found here 12 MSI-H cases (12/603, 2%). Of interest, we demonstrated that this phenotype was specifically associated with immunodeficiency-related lymphomas (ID-RL), because it was observed in both posttransplant lymphoproliferative disorders (9/111, 8.1%) and HIV infection-related lymphomas (3/128, 2.3%) but not in a large series of NHL arising in the general population (0/364) (P < 0.0001). The MSI pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSI-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, MSI-H ID-RL were found to harbor such genetic alterations in 12 target genes with a putative role in lymphomagenesis. The observation that the MSI-H phenotype was restricted to HIV infection-related lymphomas and posttransplant lymphoproliferative disorders suggests the existence of the highly immunogenic mutator pathway as a novel oncogenic process in lymphomagenesis whose role is favored when host immunosurveillance is reduced. Because MSI-H-positive cases were found to be either Epstein-Barr virus-positive or -negative, the mutator pathway should act synergistically or not with this other oncogenic factor, playing an important role in ID-RL.
Duval
Alex
A
Institut National de la Santé et de la Recherche Médicale U434, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France. alex.duval@cephb.fr
Raphael
Martine
M
Brennetot
Caroline
C
Poirel
Helene
H
Buhard
Olivier
O
Aubry
Alban
A
Martin
Antoine
A
Krimi
Amor
A
Leblond
Veronique
V
Gabarre
Jean
J
Davi
Frederic
F
Charlotte
Frederic
F
Berger
Francoise
F
Gaidano
Gianluca
G
Capello
Daniela
D
Canioni
Danielle
D
Bordessoule
Dominique
D
Feuillard
Jean
J
Gaulard
Philippe
P
Delfau
Marie Helene
MH
Ferlicot
Sophie
S
Eclache
Virginie
V
Prevot
Sophie
S
Guettier
Catherine
C
Lefevre
Pascale Cornillet
PC
Adotti
Francoise
F
Hamelin
Richard
R
D000328:Adult; D000368:Aged; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D016368:Frameshift Mutation; D015658:HIV Infections / Q000150:complications*; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D016867:Immunocompromised Host; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000235:genetics* / Q000821:virology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype
D017931:DNA Primers