title: An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.
abstract: OBJECTIVE
  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 O(6)-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.
  
  
  METHODS
  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 O(6)-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 O(6)-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.
authors.affiliation: Leukaemia Research Fund Epidemiology and Genetics Unit, Academic Unit of Epidemiology, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Worrillow
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Smith
authors.forename: Sara
authors.initials: S
authors.lastname: Rollinson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wild
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Holowaty
authors.forename: Betsy A
authors.initials: BA
authors.lastname: Kohler
authors.forename: Tom
authors.initials: T
authors.lastname: Wiklund
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.forename: Eve
authors.initials: E
authors.lastname: Roman
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
mesh_terms: D000293:Adolescent; D000328:Adult; D000477:Alkylating Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D004260:DNA Repair; D005091:Exons; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007938:Leukemia / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012306:Risk; D017422:Sequence Analysis, DNA; D012689:Sequence Homology, Nucleic Acid
chemical_list: D000477:Alkylating Agents