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An Intron Splice Acceptor Polymorphism in hMSH2 and Risk of Leukemia after Treatment with Chemotherapeutic Alkylating Agents¹

Leukaemia Research Fund Epidemiology and Genetics Unit [L. J. W., A. G. S., S. R., E. R., G. J. M., J. M. A.] and Molecular Epidemiology Unit, Academic Unit of Epidemiology and Health Services Research [A. J. S., C. P. W.], School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom; Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892 [L. B. T.]; Cancer Care Ontario, Toronto, Ontario, Canada [E. J. H.]; New Jersey Department of Health and Senior Services, Trenton, New Jersey [B. A. K.]; Helsinki University Central Hospital, Helsinki, Finland [T. W.]; and the Finnish Cancer Registry, Helsinki, Finland [E. P.]

Purpose: We sought to determine whether the -6 exon 13 T>C polymorphism in the DNA mismatch repair gene hMSH2 modulates susceptibility to acute myeloid leukemia after therapy and particularly after O⁶-guanine alkylating chemotherapy. We also determined the extent of microsatellite instability (MSI) in therapy-related acute myeloid leukemia (t-AML) as a marker of dysfunctional DNA mismatch repair.

Experimental Design: Using a novel restriction fragment length polymorphism, verified by direct sequencing, we have genotyped 91 t-AML cases, 420 de novo acute myeloid leukemia cases, and 837 controls for the hMSH2 -6 exon 13 polymorphism. MSI was evaluated in presentation bone marrow from 34 cases using the mononucleotide microsatellite markers BAT16, BAT25, and BAT26.

Results: Distribution of the hMSH2 -6 exon 13 polymorphism was not significantly different between de novo acute myeloid leukemia cases and controls, with heterozygotes and homozygotes for the variant (C) allele representing 12.2 and 1.6%, respectively, of the control population. However, the variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O⁶-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (odds ratio, 4.02; 95% confidence interval, 1.40–11.37). Thirteen of 34 (38%) t-AML cases were MSI positive, and 2 of these 13 cases were homozygous for the variant (C) allele, a frequency substantially higher than in the control population.

Conclusions: Association of the hMSH2 -6 exon 13 variant (C) allele with leukemia after O⁶-guanine alkylating agents implicates this allele in conferring a nondisabling DNA mismatch repair defect with concomitant moderate alkylation tolerance, which predisposes to the development of t-AML via the induction of DNA mismatch repair-disabling mutations and high-grade MSI. Homozygosity for the hMSH2 variant in 2 of 13 MSI-positive t-AML cases provides some support for this model.

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