An intron splice acceptor polymorphism in hMSH2 and risk of leukemia after treatment with chemotherapeutic alkylating agents.
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.
Worrillow
Lisa J
LJ
Leukaemia Research Fund Epidemiology and Genetics Unit, Academic Unit of Epidemiology, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
Travis
Lois B
LB
Smith
Alexandra G
AG
Rollinson
Sara
S
Smith
Andrew J
AJ
Wild
Christopher P
CP
Holowaty
Eric J
EJ
Kohler
Betsy A
BA
Wiklund
Tom
T
Pukkala
Eero
E
Roman
Eve
E
Morgan
Gareth J
GJ
Allan
James M
JM
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
D000477:Alkylating Agents