Identification and Characterization of Single Nucleotide Polymorphisms (SNPs) Associated with Genetic Predisposition to Develop Therapy-Related Acute Myeloid Leukemia (t-AML).

Introduction: Polymorphisms in certain genes involved on chemo/radio therapy response, as genes involved on DNA synthesis and repair, oxidative stress and drug detoxification, could be related to increased risk of develop t-AML.

Objectives: To identified SNPs on genes that could be involved on putative risk of developing t-AML. To analyse the influence of relevant polymorphisms between groups of patients depending of the intensity and the type of treatment received.

Material and Methods: Twelve polymorphisms located on genes from drug detoxification pathways (NOQ1, GSTP1), DNA repair (XPC[3], XRCC1[2], NBS1, ERCC5 and XRCC3) and DNA synthesis (MTHFR[2]) were studied. The analysis was carried out by restriction fragment length polymorphisms (RFLP). The analysed groups were A) 29 patients with t- AML: 19 haematological malignancies (A1) and 10 breast cancers (A2); B) control group, composed by 38 patients treated of a primary cancer with chemo/radio therapy ± autologous stem cell transplantation (ASCT) which after a period of ten years have not developed a t-AML: 26 haematological malignancies (B1) and 12 breast cancers (B2); C) 50 healthy individuals.

Results: Five SNPs were found to be relevant, as is shown in the table. The two SNPs on MTHFR gene (667C/T y 1298A/C) displayed remarkably different allele frequencies between the groups of breast cancer patients (with and without t-AML), while no significant differences were observed when those primary cancer were haematological. XRCC1 displayed a low frequency of A in t-AML patients with haematological cancer when are treated with ASCT, compared with those not ASCT treated. This difference is also relevant when all group of patients with hematological malignancies are analysed (A1+B1+ASCT vs no ASCT) (p=0.014). Differences on allele frequencies in SNPs of ERCC5 and NBS1 genes between t-AML and non t-AML patients we observed only when haematological neoplasia patients are ASCT treated.

Relevant SNPs found in t-AML

Conclusions: The SNPs on MTHFR gene seem to be related on gene predisposition to t-AML only on breast cancer patients. In haematological malignancies, XRCC1 E10 genotype seems be related with survival in ASCT treated patients and risk of developing t-AML for those patients treated with lower intensity. The SNPs on ERCC5 and NBS1 genes seem to be involved on t-AML predisposition in ASCT treated patients. Thus, while XRCC1, NBS1 and ERCC5 SNPs are related with the development of t-AML on those patients with previous haematological malignancies (treated mainly with alkylating agents), MTHFR SNPs are related with t-AML on those patients with previous breast cancer (treated mainly with topoisomerase II inhibitors), suggesting that the relevance of each SNP depends on differences on type of chemotherapy, intensity and the metabolic route in which they are involved. Supported by FIS G03/008 project.