Mathonnet Géraldine, Krajinovic Maja, Labuda Damian, Sinnett Daniel
Service d'Hématologie-Oncologie, Centre de Cancérologie Charles-Bruneau, Centre de Recherche, Hôpital Sainte-Justine, and Département de Pédiatrie, Université de Montréal, Montréal, Québec, Canada.
Br J Haematol. 2003 Oct;123(1):45-8. doi: 10.1046/j.1365-2141.2003.04551.x.
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Genetic variants in the coding regions of the mismatch repair genes MLH1 (Ile-219Val) and MSH3 (Arg-940Glu and Thr-1036Ala) could contribute to an individual's susceptibility as modifiers in leukaemogenesis. To investigate this possibility, we conducted a case-control study on 287 children with ALL and 320 healthy controls both of French-Canadian origin. MLH1 and MSH3 variants, when taken independently, seemed to play little or no role in the aetiology of childhood ALL. However, when the MLH1 genotypes were combined with genotypes previously shown to influence ALL susceptibility, we found that the MLH1 variant Val-219 further increases the risk of GSTM1 null and CYP1A12A genotypes [combined odds ratio (OR) = 6.0, P = 0.002] as well as that of CYP2E15 (OR = 15.8, P = 0.001). No association was found with MSH3 variants. This study suggests an association of leukaemogenesis in children with both xenobiotic metabolism and DNA repair, and thus points to the effect of environmental exposure.
急性淋巴细胞白血病（ALL）是儿童期最常见的癌症。错配修复基因MLH1（Ile-219Val）和MSH3（Arg-940Glu和Thr-1036Ala）编码区的基因变异可能作为白血病发生过程中的修饰因子，影响个体易感性。为了探究这种可能性，我们对287名法裔加拿大儿童ALL患者和320名健康对照儿童进行了一项病例对照研究。单独来看，MLH1和MSH3变异似乎在儿童ALL病因学中作用很小或不起作用。然而，当将MLH1基因型与先前已证明会影响ALL易感性的基因型相结合时，我们发现MLH1变异Val-219会进一步增加GSTM1缺失和CYP1A12A基因型的风险[合并比值比（OR）=6.0，P=0.002]以及CYP2E15的风险（OR=15.8，P=0.001）。未发现与MSH3变异存在关联。这项研究表明儿童白血病发生与外源性物质代谢和DNA修复均有关联，因此指出了环境暴露的影响。
