Genetic Factors in the Etiology of Childhood Acute B Cell Progenitor Lymphoblastic Leukemia. Summary of the Doctoral Thesis

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood. More than 80% of children diagnosed with ALL can be cured with current multiagent regimens. Despite numerous studies very little is still known about etiology of ALL. It is thought that initiation of leukemogenesis occurs during fetal life or in early infancy and is likely caused by interactions between exogenous or endogenous exposures, genetic (inherited) susceptibility. The heritable basis of susceptibility to ALL is further supported by recent candidate gene and genome wide association studies (GWAS), suggesting that co-inheritance of multiple germline variants may contribute to the risk of the disease. One potentially important genetic pathway suspected in playing a role in childhood ALL is xenobiotic metabolism. Our cohort consisted of 77 patients with childhood B cell progenitor cells ALL in complete remission, and 122 age and gender adjusted healthy controls. In addition, parental DNA was available for 50 probands. Patients were diagnosed with ALL between 2005 and 2014, aged 0-18 years at that time. Our study covered 91.67% of all patients. To separate study models case – control and case – parent study was used to analyse genetical factors which might contribute risk of childhood leukaemia. To increase statistical power hybrid model, was used to analyse results from both models at once. To analyse previously described polymorphisms from GWAS and polymorphisms which are involved in xenobiotic metabolism by decreasing enzyme activity polymerase chain reaction with subsequent restriction fragment length polymorphism analysis was performed, or polymorphisms were analysed by sequencing reaction. During this study in total twenty two polymorphisms were analysed located in genes: ARID5B, IKZF1, CEBPE, CDKN2A, MTHFR, MDR1, GSTT1, GSTM1, NOQ1, IL15 and PAX5. This is a first time when full IKZF1 gene sequencing was performed to search germline mutations as well as Ikaros expression analysis. As a result we found out that most frequently affected children are born in the 2004. Between the analysed polymorphisms only polymorphism rs2032582 located in gene MDR1 might be associated with development of high risk leukaemia. Polymorphisms located in gene ARID5B were strongly associated with increased leukaemia risk, so were their haplotypes. This is the first study were possible association between polymorphisms rs10821937 and rs7908445 and leukaemia was investigated. These results replicate results from previous studies, but cannot explain mechanism how pathogenesis of leukaemia can be influenced by these single nucleotide polymorphisms. During this study we identified possible risk combinations of polymorphisms rs3731217, rs2239633, rs4132601, rs10821936 and rs10994982 which might contribute susceptibility of leukaemia. Analysis of polymorphisms in genes MDR1 and MTHFR showed some risk and protective haplotypes, as well pointed out influence of mother genotype. Analysis of IL15 showed some protective haplotypes. We could not identify any pathogenic mutations in gene IKZF1 but we were able to discover some genetical variants which might affect splicing activity, two of them were polymorphisms rs199614380 and rs7789106, on was indel rs72334180, and two of them were located in exon 8, they were synonyms variants rs61731355 and rs61731356. None of the investigated polymorphisms show association with protein level and none of the children in complete remission had total lack of this protein.