Polimorfismos em genes de reparo do DNA e risco para leucemias agudas infantis e do lactente

Abstract

Early age acute leukemia (e-AL; up to 24 months old) and infant acute leukemia (i-AL; up to 12 months old) have a high frequency of chromosomal rearrangements envolving Lysine specific methyltransferase 2A gene (KMT2A, previously termed as MLL), which has an important role on epigenetics both in fetal development and definitive hematopoiesis. KMT2A rearrangements (KMT2A-r) occur both in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Single strand breaks and double strand breaks caused by parental exposition to xenobiotics compounds during pregnancy are repaired by base excision repair (BER), nucleotide excision repair (NER) and non-homologous end-joining (NHEJ) systems. NHEJ is an error-prone repair system enrolled in chromosomal translocations, including KMT2A-r. To test the hypothesis that genetic variants on DNA repair systems modify the risk for e-AL and i-AL, we investigated rs25487 (XRCC1), rs11615 (ERCC1), rs3212986 (ERCC1), rs5751129 (XRCC6), rs6869366 (XRCC4) and rs28360071 (XRCC4) in association with KMT2A-r and leukemia risk to these two conditions. Using data from BCSGIAL (2000-2013), 277 cases (ALL = 164; AML = 113) and 300 controls up to 24 months old were genotyped by PCR or PCR-RFLP. Bone marrow XRCC4 expression was evaluated by qPCR. Hardy-Weinberg equilibrium was calculated using GenPop Web 4.5.1, Odds ratio (OR) were calculated using SPSS Statistics 22.0, and gene expression was analyzed on GraphPad Prism 5. We have found that rs3212986 (recessive model: p = 0.013; aOR = 0.15; CI: 0.03-0.67; CCxAA model: p < 0.010; ORa = 0.13; CI: 0.03-0.58) has a protective effect for e-AL; and rs25487 demonstrated a global increased risk for AML (recessive model: p < 0,001; aOR 6.30; CI: 3.25-12.2). The rs28360071 variant increases the risk to e-ALL and i-ALL in children harboring KMT2A-r (II x ID model: p = 0.014; aOR 2.23; CI: 1.17-4.25; p = 0.031 aOR = 2.27; CI: 1.07-4.82, respectively). The remaining variants did not showed any statistical significance with the risk. ALL patients showed a higher bone marrow expression level of XRCC4 mRNA, but there was no differences regarding rs28360071 genotypes. Human Splicing Finder 3.1 software predicted that the deletion allele is potentially associated with the activation of a donor cryptic splice site in intron 3, which could contribute to protein structure and function modifications. These data point to a relationship between rs25487 and rs3212986 polymorphisms and acute leukemia, and an association of rs28360071 and ALL with KMT2A-r.