Human mismatch repair, drug-induced DNA damage, and secondary cancer.
DNA mismatch repair (MMR) is an important replication error avoidance mechanism that prevents mutation. The association of defective MMR with familial and sporadic gastrointestinal and endometrial cancer has been acknowledged for some years. More recently, it has become apparent that MMR defects are common in acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS) that follows successful chemotherapy for a primary malignancy. Therapy-related haematological malignancies are often associated with treatment with alkylating agents. Their frequency is increasing and they now account for at least 10% of all AML cases. There is also evidence for an association between MMR deficient AML/MDS and immunosuppressive treatment with thiopurine drugs. Here we review how MMR interacts with alkylating agent and thiopurine-induced DNA damage and suggest possible ways in which MMR defects may arise in therapy-related AML/MDS.
Karran
Peter
P
Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts EN6 3LD, UK. peter.karran@cancer.org.uk
Offman
Judith
J
Bignami
Margherita
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology
D000970:Antineoplastic Agents