BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for @entity978 , but are associated with the development of second @entity5 . @entity137 of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of @entity6756 , 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 @entity6756 (position -93, @entity65181 ) modifies the risk of @entity5 after methylating chemotherapy. METHODS: 133 @entity1 who developed @entity5 following chemotherapy and/or radiotherapy (n = 133), 420 @entity1 diagnosed with de novo @entity1778 , 242 @entity1 diagnosed with primary @entity978 , and 1177 healthy controls were genotyped for the @entity6756 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for @entity5 risk by @entity6756 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the @entity6756 -93 variant was higher in @entity1 who developed @entity3052 ( @entity3052 ) (75.0%, n = 12) or @entity0 (53.3%. n = 15) after methylating chemotherapy for @entity978 compared to @entity1 without previous methylating exposure ( @entity3052 , 30.4%, n = 69; @entity0 @entity1 , 27.2%, n = 22). The @entity6756 -93 variant allele was also over-represented in @entity3052 cases when compared to de novo @entity3052 cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing @entity3052 (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in @entity1 previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of @entity6756 defines a risk allele for the development of @entity5 after methylating chemotherapy for @entity978 . However, replication of this finding in larger studies is suggested.

Polymorphic @entity6756 and risk of XXXX after methylating chemotherapy for @entity978 .

@entity65181 :: ('rs1800734', 'SNP') :: ['rs1800734'] @entity6756 :: ('4292', 'Gene') :: ['MLH1'] @entity1 :: ('9606', 'Species') :: ['patients'] @entity137 :: ('MESH:D064420', 'Disease') :: ['Cytotoxicity'] @entity0 :: ('MESH:D001943', 'Disease') :: ['breast cancer'] @entity5 :: ('MESH:D009369', 'Disease') :: ['primary cancers', 'cancer'] @entity3052 :: ('MESH:D015470', 'Disease') :: ['therapy related acute myeloid leukaemia', 'AML', 't-AML'] @entity1778 :: ('MESH:D007938', 'Disease') :: ['myeloid leukaemia'] @entity978 :: ('MESH:D006689', 'Disease') :: ['Hodgkin lymphoma']
@entity5 :: (MESH:D009369,Disease) :: ['cancer']
