Background and objective: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy.
Methods: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression.
Results: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent.
Conclusions: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
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Author contributions: LJW designed and performed research. AGS designed research and analysed data. KS performed research. LBT was principal investigator of the Hodgkin lymphoma-breast cancer study. JMA developed the hypothesis, coordinated the study, designed research and performed research. All other authors are listed alphabetically, each making a significant contribution to one of the individual components of the study (leukaemia or breast cancer). GJM contributed to the identification and collection of therapy related leukaemia cases.
Funding: We acknowledge the support of the Medical Research Council DNA/RNA bank (University College London Hospital), a facility funded by the Kay Kendall Leukaemia Fund). The leukaemia work was supported by the Leukaemia Research Fund of the United Kingdom. The breast cancer work was supported in part by the Intramural Research Program of the United States National Cancer Institute, Division of Cancer Epidemiology and Genetics.
Competing interests: None.
Ethics approval: Ethical committee approval was obtained for this study.
Patient consent: Informed consent was provided according to the Declaration of Helsinki