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Polymorphic MLH1 and risk of cancer after methylating chemotherapy for Hodgkin lymphoma
  1. Lisa Worrillow (lisa.worrillow{at}egu.york.ac.uk)
  1. York University, United Kingdom
    1. Alex Smith (alex.smith{at}egu.york.ac.uk)
    1. York University, United Kingdom
      1. Kathryn Scott (ks27{at}york.ac.uk)
      1. York University, United Kingdom
        1. Michael Andersson (michael.andersson{at}rh.hosp.dk)
        1. Danish Cancer Society, Denmark
          1. John Ashcroft (johnashcroft{at}doctors.org.uk)
          1. Pinderfields Hospital, United Kingdom
            1. Graca Dores (doresg{at}mail.nih.gov)
            1. National Cancer Institute, United States
              1. Bengt Glimelius (bengt.glimelius{at}onkologi.uu.se)
              1. Uppsala University, Sweden
                1. Eric Holowaty (eric.holowaty{at}cancercare.on.ca)
                1. Cancer Care Ontario, Canada
                  1. Graham Jackson (graham.jackson{at}newcastle.ac.uk)
                  1. Royal Victoria Hospital, United Kingdom
                    1. Gail L Jones (gail.jones{at}newcastle.ac.uk)
                    1. Royal Victoria Hospital, United Kingdom
                      1. Charles Lynch (charles-lynch{at}uiowa.edu)
                      1. University of Iowa, United States
                        1. Gareth Morgan (gareth.morgan{at}icr.ac.uk)
                        1. Institute for Cancer Research, United Kingdom
                          1. Eero Pukkala (eero.pukkala{at}cancer.fi)
                          1. Finnish Cancer Registry, Finland
                            1. Daniel Scott (ks27{at}york.ac.uk)
                            1. Harrogate and Disctrict NHS Foundation Trust, United Kingdom
                              1. Hans Storm (hans{at}cancer.dk)
                              1. Aalborg Hospital, Denmark
                                1. Penny Taylor (pennytaylor{at}doctors.org.uk)
                                1. Royal Victoria Infirmary, United Kingdom
                                  1. Mogens Vyberg (mv{at}rn.dk)
                                  1. Aalborg Hospital, Denmark
                                    1. Eleanor Willett (eleanor.willett{at}egu.york.ac.uk)
                                    1. York University, United Kingdom
                                      1. Lois Travis (travis1122{at}optonline.net)
                                      1. National Cancer Institute, United States
                                        1. James Allan (james.allan{at}ncl.ac.uk)
                                        1. Newcastle University, United Kingdom

                                          Abstract

                                          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 mutagenized cells at high risk of malignant transformation. We hypothesized that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. Methods: One hundred and thirty three 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 PCR and restriction fragment length polymorphism assay. Odds ratios (ORs) and 95% confidence intervals (CIs) 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 (OR 5.31, 95% CI 1.40-20.15), 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.

                                          • chemotherapy
                                          • genetic polymorphism
                                          • radiotherapy
                                          • second primary cancer
                                          • therapy-related

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