Biomedical subjects

Maja Krajinovic

Publications and source records attributed to Maja Krajinovic.

22 records · Page 2Linked to original sources

PubMed2002

Role of NQO1, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The genetic factors underlying the susceptibility to this disease remain elusive. The enzymes CYP2E1, MPO and NQO1 are involved in the biotransformation of a variety of xenobiotics present in organic solvents, tobacco smoke, drugs, plastic derivatives and pesticides. They also control the level of the oxidative stress by catalyzing the formation of free radicals or by protecting cells from their deleterious effect. DNA variants in the corresponding genes have been associated with an increased susceptibility to different adult cancers, including hematologic malignancies. To investigate whether they represent risk-modifying factors in childhood ALL, we conducted a case-control study involving 174 patients and 337 controls, both of French-Canadian origin. We found that carriers of the CYP2E1*5 variant were at 2.8-fold higher risk of ALL (95%CI, 1.2-6.4) and that NQO1 alleles *2 and *3 contributed to the risk of ALL as well (OR = 1.7, 95%CI, 1.2-2.4). No such association was found with MPO alone. However, when the wild-type MPO allele was considered together with the CYP2E1 and NQO1 risk-elevating genotypes, the risk of ALL was increased further (OR = 5.4, 95%CI, 1.2-23.4) suggesting a combined effect. We also found a gene-gene interaction between the GSTM1 null genotype and NQO1 mutant alleles. It is therefore plausible that exposure to xenobiotics metabolized by these enzymes play a role in the etiology of childhood ALL.

Case-Control Studies↗

PubMed2002

Childhood acute lymphoblastic leukemia associated with parental alcohol consumption and polymorphisms of carcinogen-metabolizing genes.

BACKGROUND: Limited information is available on the association of parental consumption of alcohol prior to and during pregnancy with the risk of childhood leukemia, as well as for the potentially modifying role of genetic polymorphisms. METHODS: We conducted a population-based, case-control study of 491 incident cases of acute lymphoblastic leukemia age 0-9 years and matched on age and sex to 491 healthy controls. Cases were identified at tertiary care centers in the Province of Québec between 1980 and 1993. Each parent was interviewed separately about alcohol consumption habits. We also used a case-only design with 186 cases to estimate interaction odds ratios between prenatal exposure and child DNA variants in the GSTM1 and CYP2E1 genes. RESULTS: The adjusted odds ratio for any maternal consumption during pregnancy was 0.7 (95% confidence interval = 0.5-0.9). The interaction odds ratios for the GSTM1 null genotype during third pregnancy trimester was 2.4 (95% confidence interval = 1.1-5.4); the interaction odds ratio for CYP2E1 variant G-1295C (or allele *5) during the nursing period was 4.9 (95% confidence interval = 1.5-16.7). CONCLUSIONS: The observed association with maternal alcohol consumption during pregnancy could be due to the potential chemopreventive effects of flavonoids found in wine and beer. These possible effects of alcohol may be at least partially genetically determined, although data are preliminary.

Alcohol Drinking↗

PubMed2002

Glutathione S-transferase P1 genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukaemia.

Glutathione S-transferase pi (GSTP1) is involved in the metabolism of carcinogens. We assessed the association of GSTP1 genetic polymorphisms and the susceptibility to childhood acute lymphoblastic leukaemia (ALL) by conducting a case-control study on 278 ALL patients and 303 healthy controls, both of French-Canadian origin. The carriers of the GSTP1*B variant (only the Val105 substitution) were found to be associated with an increased risk of ALL [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.0], whereas the GSTP1*C variant (both Val105 and Val114) was underrepresented in cases. Thus, genetic variants of GSTP1 that are expressed at the protein level appear to contribute differently to the risk of ALL, probably because of distinct substrate specificities. When combined with other GST genotypes, we found that the combination of GSTP1*B and GSTM1 null genotypes further increased the risk of ALL (OR = 2.1; 95% CI-1.3-3.4). These findings suggest that GSTP1 variants (alone or combined with other GSTs) represent significant genetic determinants of childhood ALL.

Base Sequence↗

PubMed2002

Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia.

PURPOSE: The most common childhood malignancy, acute lymphoblastic leukemia (ALL), remains the leading cause of cancer-related death in children because of resistant cases in which underlying predisposing factors are poorly understood. The interindividual variation in the activity of xenobiotic metabolizing enzymes that modify individual somatic mutation burden in the context of environmental exposure was shown to modify susceptibility to childhood ALL. Variable DNA repair capacity may further modulate induced DNA lesions. Similarly, differential capacity of ALL patients to process carcinogens and chemotherapeutic drugs could both modify an individual's risk of recurrent malignancy and response to therapy. EXPERIMENTAL DESIGN: We investigated the relationship between the risk of relapse in ALL patients and functional polymorphisms in genes encoding carcinogen-metabolizing enzymes, including CYP1A1, CYP2D6, CYP2E1, MPO, GSTM1, GSTT1, GSTP1, NAT1, NAT2, NQO1, as well as DNA-repair enzymes hMLH1, hMSH3, XRCC1, XPF, and APE. Our study included 320 children with ALL, of which 68 relapsed or died because of this disease within 5 years of follow-up. RESULTS: Among children of the latter group, we found that carriers of CYP1A1*2A and NQO1*2 variants had worse disease prognosis according to Kaplan-Meier (P = 0.003) and Cox regression (P <or= 0.03) analyses. hMLH1 Ile219 contributed to the increased risk of relapse when combined with the CYP1A1*2A variant. CONCLUSIONS: Our findings suggest that determining individual genotypes can become important in predicting disease outcome. Genotyping could also guide the therapeutic protocol.

Acetyltransferases↗