Worrillow Lisa J, Travis Lois B, Smith Alexandra G, Rollinson Sara, Smith Andrew J, Wild Christopher P, Holowaty Eric J, Kohler Betsy A, Wiklund Tom, Pukkala Eero, Roman Eve, Morgan Gareth J, Allan James M
Leukaemia Research Fund Epidemiology and Genetics Unit, Academic Unit of Epidemiology, School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
Clin Cancer Res. 2003 Aug 1;9(8):3012-20.
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.
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.
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.
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.
我们试图确定DNA错配修复基因hMSH2中-6外显子13 T>C多态性是否会调节治疗后尤其是O(6)-鸟嘌呤烷基化化疗后急性髓系白血病的易感性。我们还确定了治疗相关急性髓系白血病（t-AML）中微卫星不稳定性（MSI）的程度，作为DNA错配修复功能障碍的标志物。
我们使用一种经直接测序验证的新型限制性片段长度多态性方法，对91例t-AML病例、420例初发急性髓系白血病病例和837例对照进行了hMSH2 -6外显子13多态性的基因分型。使用单核苷酸微卫星标记BAT16、BAT25和BAT26对34例病例的初诊骨髓进行了MSI评估。
初发急性髓系白血病病例与对照之间hMSH2 -6外显子13多态性的分布无显著差异，变异（C）等位基因的杂合子和纯合子分别占对照人群的12.2%和1.6%。然而，与对照相比，先前接受过包括环磷酰胺和丙卡巴肼在内的O(6)-鸟嘌呤烷基化剂治疗的t-AML病例中，变异（C）hMSH2等位基因的比例显著过高（优势比，4.02；95%置信区间，1.40 - 11.37）。34例t-AML病例中有13例（38%）MSI呈阳性，其中13例中的2例变异（C）等位基因为纯合子，该频率显著高于对照人群。
hMSH2 -6外显子13变异（C）等位基因与O(6)-鸟嘌呤烷基化剂治疗后的白血病相关，这表明该等位基因会导致一种非致残性DNA错配修复缺陷，并伴有适度的烷基化耐受性，通过诱导DNA错配修复失活突变和高度MSI，易引发t-AML的发生。13例MSI阳性t-AML病例中有2例hMSH2变异为纯合子，为该模型提供了一些支持。
