Azathioprine induction of tumors with microsatellite instability: risk evaluation using a mouse model.
Mismatch-repair (MMR)-deficient cells show increased in vitro tolerance to thiopurines because they escape apoptosis resulting from MMR-dependent signaling of drug-induced DNA damage. Prolonged treatment with immunosuppressants including azathioprine (Aza), a thiopurine prodrug, has been suggested as a risk factor for the development of late onset leukemias/lymphomas displaying a microsatellite instability (MSI) phenotype, the hallmark of a defective MMR system. We performed a dose effect study in mice to investigate the development of MSI lymphomas associated with long term Aza treatment. Over two years, Aza was administered to mice that were wild type, null or heterozygous for the MMR gene Msh2. Ciclosporin A, an immunosuppressant with an MMR-independent signaling, was also administered to Msh2(wt) mice as controls. Survival, lymphoma incidence and MSI tumor phenotype were investigated. Msh2(+/-) mice were found more tolerant than Msh2(wt) mice to the cytotoxicity of Aza. In Msh2(+/-) mice, Aza induced a high incidence of MSI lymphomas in a dose-dependent manner. In Msh2(wt) mice, a substantial lifespan was only observed at the lowest Aza dose. It was associated with the development of lymphomas, one of which displayed the MSI phenotype, unlike the CsA-induced lymphomas. Our findings define Aza as a risk factor for an MSI-driven lymphomagenesis process.
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Sahra
S
Bodo
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France.
Magali
M
Svrcek
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Isabelle
I
Sourrouille
AP-HP, Institut Gustave Roussy, Service d'Anatomie Pathologique, F-94805 Villejuif, France.
Peggy
P
Cuillières-Dartigues
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Tatiana
T
Ledent
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|IFR 65, F-75012 Paris, France.
Sylvie
S
Dumont
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Laetitia
L
Dinard
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Philippe
P
Lafitte
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Camille
C
Capel
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Ada
A
Collura
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Olivier
O
Buhard
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Kristell
K
Wanherdrick
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Alexandra
A
Chalastanis
INSERM, U985, Institut Gustave Roussy, F-94805 Villejuif, France.
Virginie
V
Penard-Lacronique
AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France.
Bettina
B
Fabiani
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine, Service d'Anatomie Pathologique, F-75012 Paris, France.
Jean-François
JF
Fléjou
AP-HP, Hôpital Necker-Enfants Malades, Service d'Anatomie Pathologique, F-75015 Paris, France.
Nicole
N
Brousse
Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.|AP-HP, Hôpital Saint-Antoine, Service de Gastroentérologie, F-75012 Paris, France.
Laurent
L
Beaugerie
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Alex
A
Duval
INSERM, UMR_S 938, CDR Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, F-75012 Paris, France.
Martine
M
Muleris
D000328:Adult; D000368:Aged; D000818:Animals; D001379:Azathioprine / Q000633:toxicity*; D053843:DNA Mismatch Repair / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000633:toxicity; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D053842:Microsatellite Instability; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
D007166:Immunosuppressive Agents; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D001379:Azathioprine
azathioprine; iatrogenic cancer; microsatellite instability; pharmacogenetics; thiopurine tolerance