Research Article: Association Study of Xenobiotic Detoxication and Repair Genes with Malignant Brain Tumors in Children

Date Published: , 2010

Publisher: A.I. Gordeyev

Author(s): L.E. Salnikova, N.I. Zelinskaya, O.B. Belopolskaya, M.M. Aslanyan, A.V. Rubanovich.

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Abstract

This study presents the results of research on DNA polymorphism in children with malignant brain tumors (172 patients, 183 in the control group). Genotyping was performed using an allele-specific tetraprimer reaction for the genes of the first (CYP1A1 (2 sites)) and second phases of xenobiotic detoxication (GSTM1, GSTT1, GSTP1, GSTM3), DNA repair genesXRCC1, XPD(2 sites),OGG1, as well asNOS1andMTHFR.The increased risk of disease is associated with a minor variant ofCYP1A1(606G) (p = 0.009; OR = 1.50) and a deletion variant ofGSTT1, (p = 0.013, OR = 1.96). Maximum disease risk was observed in carriers of double deletions inGSTT1-GSTM1(p = 0.017, OR = 2.42). The obtained results are discussed in reference to literary data on the risk of malignant brain tumor formation in children and adults.

Partial Text

The causes behind the formation of malignant tumors of the central nervous system (CNS) in children, of which 80% are cerebral tumors, are unknown. Risk factors for this type of pathology include inherited susceptibility and the effects of irradiation. Several genetic syndromes, such as the Li-Fraumeni syndrome, Turcot syndrome, neurofibromatosis, and tuberous sclerosis, are known to cause CNS tumors. Moreover, there are families with an increased risk of cerebral tumor formation. For instance, a population cohort from Utah (USA) and a tumor register, which was created based on data from this cohort, indicate the importance of the inheritance factor in most common malignant diseases of the brain in adults (astrocytomas and glioblastomas) [1]. Studies of the Swedish tumor register indicate that first-degree relatives are 2 to 3 times more likely to develop a brain tumor of the same histopathological type as their probands [2]. The offspring of people who had a brain tumor in their childhood are twice as likely to develop a similar tumor [3], the same being true for such a patient’s siblings, especially before the age of 5.

A cohort of 172 children with malignant CNS tumors (92 boys and 80 girls) aged 2-16 were included in this study. These children were under treatment in the laboratory of the Children’s X-ray Radiology of the Russian Scientific Center ofRoentgenoradiology from 2007 to 2010. The average age of the child patients was 8.96±0.38. The most common tumors in the studied cohort were medulloblastomas ( N = 58) and brain stem tumors ( N = 26). Apart from these, there were also cases of apoplastic ependymoma ( N = 19), glioblastoma ( N = 10), germinogenic tumors ( N = 6), low malignancy astrocytoma ( N = 5), high malignancy astrocytoma ( N = 5), primitive neuroectodermal tumors ( N = 5), and others ( N = 38). The control group consisted of 183 people (102 males and 81 females) aged 17 to 21, an average age of 19.90 ± 0.08 years. All the sick children and youths from the control group were of Caucasian race. The patient database contains information on their places of birth and residence. The children’s parents gave informed consent for the genotyping procedure. The ten-year difference in the average age of the patient and control groups could not have any significant effect on the allelic variant frequencies in the groups, since mortality in this age group does not exceed 0.1% (Table 2) [28]. Moreover, the first four main causes of death in the 15–24-age group are violence-related: unintentional bodily harm, suicide, undefined bodily harm and murder [29]. The criteria for involvement into the control group were age, nationality, birthplace inside the central regions of the European territory of the Russian Federation, and informed consent to the procedures.

We identified the genotypes of the studied individuals at 12 polymorphic sites of 10 genes. The genotype frequencies in the control group and the patient group were in accordance with the Hardy-Weinberg distribution.

The detoxification of xenobiotics consists of two main stages of detoxification and a third stage – secretion of the detoxified products out of the cell. The first stage involves activation of the xenobiotic compounds by P-450 cytochromes and a number of other enzymes. The second stage is the detoxification, per se, and it involves glutathione-S-transferases and other proteins. The intermediary electrophilic metabolites that were formed in the first stage are toxic, and effective detoxification requires a fine balance between the activity of the first- and second-stage enzymes. This balance is deregulated both by insufficient activity of the polymorphic variants of the second-stage enzymes and by the increased activity of the first-stage enzymes [31]. Increased activity of the first-stage detoxification enzymes and insufficient activity of the second-stage enzymes (GST) cause an increase in the level of activated electrophilic metabolites, thus increasing the deleterious effects of the xenobiotic compounds.

 

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