The mechanisms underlying MMR deficiency in immunodeficiency-related non-Hodgkin lymphomas are different from those in other sporadic microsatellite instable neoplasms.
The spectrum of tumors showing microsatellite instability (MSI) has recently been enlarged to sporadic neoplasms whose incidence is favored in the context of chronic immunosuppression. We investigated the biological, therapeutic and clinical features associated with MSI in immunodeficiency-related non-Hodgkin lymphomas (ID-RL). MSI screening was performed in 275 ID-RL. MSI ID-RL were further analyzed for MMR gene expression and for BRAF/KRAS mutations since these genes are frequently altered in MSI cancers. We also assessed the expression of O(6)-methylguanine-DNA methyltransferase (MGMT), an enzyme whose inactivation has been reported in lymphomas and may help in the selection of MMR deficient clones. Unlike other sporadic MSI neoplasms, MSI ID-RL (N = 17) presented with heterogeneous MMR defects and no MLH1 promoter methylation. About one third of these tumors presented with normal expression of MLH1, MSH2, MSH6 and PMS2. They accumulated BRAF activating mutations (33%). Unlike other ID-RL, MSI ID-RL were primarily EBV-negative NHL of T-cell origin, and arose after long-term immunosuppression in patients who received azathioprine as part of their immunosuppressive regimen (p = 0.05) and/or who exhibited methylation-induced loss of expression of MGMT in tumor cells (p= 0.02). Overall, these results highlight that, in the context of deficient immune status, some MSI neoplasms arise through alternative mechanism when compared to other sporadic MSI neoplasms. They give the exact way how to make the diagnosis of MSI in these tumors and may help to define biological and clinicalrisk factors associated with their emergence in such a clinicalcontext.
Borie
Claire
C
INSERM, UMR_S 938, Team Microsatellite Instability and Cancers, Paris, France.
Colas
Chrystelle
C
Dartigues
Peggy
P
Lazure
Thierry
T
Rince
Patricia
P
Buhard
Olivier
O
Folliot
Patrick
P
Chalastanis
Alexandra
A
Muleris
Martine
M
Hamelin
Richard
R
Mercier
Dominique
D
Oliveira
Carla
C
Seruca
Raquel
R
Chadburn
Amy
A
Leblond
Véronique
V
Barete
Stéphane
S
Gaïdano
Gianluca
G
Martin
Antoine
A
Gaulard
Philippe
P
Fléjou
Jean-François
JF
Raphael
Martine
M
Duval
Alex
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002675:Child, Preschool; D043171:Chromosomal Instability; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D055815:Young Adult; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C117307:KRAS protein, human; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes