Genetic polymorphism in GST, NAT2, and MTRR and susceptibility to childhood acute leukemia

It is known that presence of xenobiotic-metabolizing gene polymorphisms in some cases correlates with hereditary predisposition to the oncological diseases. In the present work the frequencies of xenobiotic-metabolizing gene polymorphisms in 332 children with the diagnosis acute lymphoblastic leukemia (ALL), 71 children with the diagnosis acute myeloblastic leukemia (AML) and 490 healthy donors have been determined using allele-specific hybridization on the biochip. Statistically significant increase in the frequency of GSTT1 "null" genotype (OR = 1.9, p = 4.7E-5) and GSTT1/GSTM1 double "null" genotype (OR = 3.1, p = 2.5E-8) in children with acute leukemia relative to healthy donors group has been revealed. Also 1.8-fold increase in the frequency of NAT2 genotype 341T/T, 481C/C, 590G/G in children with acute leukemia relative to healthy donors group (p = 0.026) has been recognized. Analysis of gene-gene interactions has showed that in patients with acute leukemia genotype NAT2 341T/T, 481C/C, 590G/G in combination with GSTT1 "null" and/or GSTM1 "null" genotype is significantly more frequent than in population control. Besides the reduction of MTRR genotype 66G/G frequency in girls with acute leukemia relative to female healthy donors has been found (OR = 0.50, p = 0.0015). Analysis of gene-gene interactions has shown that the presence of GSTT1 "null" and/or GSTM1 "null" genotype in combination with MTRR genotype 66A/- may consider as risk factor of acute leukemia in girls. Thus, the studied polymorphic variants of genes GSTT1, GSTM1, NAT2 and MTRR can modulate the risk of childhood acute leukemia, residents of European part of Russia.     

Evaluation of functional RAGE gene polymorphisms in childhood acute lymphoblastic leukemia—A case-control study from Iran

We examined the possible relationship between three RAGE polymorphisms, ?429C/T, ?374 T/A, and 63-bp deletion, and susceptibility to childhood acute lymphoblastic leukemia (ALL) in an Iranian population. This study included 75 ALL patients and 115 healthy subjects. Genotyping was performed using HEXA-ARMS-polymerase chain reaction. We found no significant association among RAGE gene polymorphisms and the risk for ALL at genotype, allelic and haplotype levels (P > 0.05). The hemoglobin levels were higher in patients with RAGE ?374 TT than in the TA carriers (P = 0.019). Our results demonstrated that the RAGE gene variations were not associated with risk of pediatrics ALL.     

Association of CYP3A5*3 polymorphism with development of acute leukemia

BACKGROUND:

CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5*3). We investigated the association between CYP3A5*3 polymorphism and acute leukemia.

MATERIALS AND METHODS:

Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5*3 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5*3 polymorphism and acute leukemia.

RESULTS:

The CYP3A5*3 polymorphism 3/3 genotype was significantly associated with acute leukemia development (χ²- 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL.

CONCLUSION:

The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients.     

Genetic polymorphism of GST, NAT2, and MTRR and susceptibility to childhood acute leukemia

Polymorphisms of xenobiotic-metabolizing genes correlate with hereditary predisposition to neoplasia in some cases. The frequencies of polymorphisms of xenobiotic-metabolizing genes were determined in 332 children with acute lymphoblastic leukemia, 71 children with acute myelogenous leukemia, and 490 healthy donors by allele-specific hybridization on a biochip. The frequencies of the GSTT1 null genotype and the GSTT1/GSTM1 double null genotype were significantly increased in children with acute leukemia as compared to healthy donors (OR = 1.9, P = 4.7E-5, and OR = 3.1, P = 2.5E-8, respectively). The frequency of NAT2 genotype 341T/T, 481C/C, 590G/G was increased 1.8-fold in children with acute leukemia as compared to healthy controls (P = 0.026). Analysis of gene-gene interactions showed that the combination of NAT2 genotype 341T/T, 481C/C, 590G/G with the GSTT1 and/or GSTM1 null genotypes was significantly more frequent in patients with acute leukemia than in the population control. In addition, the frequency of MTRR genotype 66G/G was reduced in girls with acute leukemia as compared to healthy female donors (OR = 0.50, P = 0.0015). The GSTT1 and/or GSTM1 null genotypes combined with MTRR genotype 66A/-were considered to be a risk factor for acute leukemia in girls. Thus, the polymorphisms of GSTT1, GSTM1, NAT2, and MTRR proved to influence the risk of childhood acute leukemia in residents of European Russia.     

The association between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia: A meta-analysis

The aim of this meta-analysis was to determine the relationship between microRNA polymorphisms and the risk of childhood acute lymphoblastic leukemia comprehensively. PubMed, EMBASE, Scopus, Web of Science, the Cochrane Library, Global Index Medicus, Clinicaltrials.gov, ProQuest, and Open Grey databases were used to find relevant papers. Using the STATA 16.0 and CMA 3.0 software, the significance of relationships between microRNA polymorphisms and childhood acute lymphoblastic leukemia risk was evaluated using odds ratios (ORs) and 95 % confidence intervals (95 % CIs) for five genetic models. The results of the meta-analysis showed that there was no significant association between the polymorphism of miR-146a rs2910164 and childhood acute lymphoblastic leukemia risk in different genetic models. Also, in the sensitivity analysis, removing Xue's study from the analysis indicated that both the homozygote and recessive models are significantly affected. Additionally, there was a statistically significant relationship between the polymorphisms of pri-miR-34b/c rs4938723 (in the homozygote and recessive models) and miR-612 rs12803915 (in the allele and dominant models) and childhood acute lymphoblastic leukemia risk. These findings suggest that the rs4938723 and rs12803915 polymorphisms may have a role in the development of childhood acute lymphoblastic leukemia.     

MIF‐173G/C (rs755622) polymorphism as a risk factor for acute lymphoblastic leukemia development in children

Background

Macrophage inhibitory factor (MIF) is a pro‐inflammatory cytokine modulating monocyte motility and a pleiotropic regulator of different biological and cellular processes. The MIF‐173G/C (rs755622) polymorphism is found in the promoter region and affects its activity. The present study investigated the MIF polymorphism as a risk factor for the development of acute lymphoblastic leukemia (ALL) in Egyptian children.

Methods

We analyzed the MIF‐173G/C (rs755622) polymorphism in 180 ALL cases and 150 healthy control children by amplification of the gene using a polymerase chain reaction followed by restriction endonuclease digestion and running on an agarose gel for visualization of the product.

Results

We found a significant incidence of the homozygous polymorphic (CC) genotype and the combined polymorphic genotypes (GC + CC) in ALL patients compared to healthy controls (p = 0.001 and p = 0.007, respectively), whereas the wild‐type genotype (GG) was more common in healthy controls (p = 0.006). Multivariate logistic regression analysis adjustment for MIF different genotypes and other potential risk factors such as age, sex and parental smoking indicated that the CC genotype is the only significant risk factor for the test (p = 0.02). We also noted that, by increasing the C‐allele representation within the gene [GC, CC], there was an increase in total leukocytic count (p = 0.09 and p = 0.001, respectively) that may reflect the bad prognostic impact of the polymorphic allele, although further studies are needed.

Conclusions

The results of the present study indicate that the MIF‐173G/C (rs755622) polymorphism is a risk factor for childhood ALL development with respect to both homozygous and combined polymorphic genotypes. In addition, the increased leukocytic count in synchronization with the increased representation of the polymorphic C‐allele may reflect its bad prognostic impact.     

The association of polymorphisms in DNA base excision repair genes <Emphasis Type="Italic">XRCC1</Emphasis>, <Emphasis Type="Italic">OGG1</Emphasis> and <Emphasis Type="Italic">MUTYH</Emphasis> with the risk of childhood acute lymphoblastic leukemia

The aim of this study was to evaluate the association of polymorphisms in genes encoding three key proteins of DNA base excision repair (BER): the OGG1 Ser326Cys, the MUTYH Tyr165Cys and the XRCC1 Arg399Gln with the risk of childhood acute lymphoblastic leukemia (ALL). Our study included 97 children patients with ALL (mean age 5.4 ± 2.5) and 131 healthy children (mean age 6.2 ± 2.8) used as controls. Genetic polymorphisms in BER pathway genes were examined using PCR and restriction fragment length polymorphism (RFLP). We have demonstrated that the OGG1 Cys/Cys genotype increases the risk of ALL (OR 5.36) whereas the Ser/Ser genotype variant strongly reduces the risk of this cancer among Polish children (OR 0.45). Although we did not observe the differences in single nucleotide polymorphisms (SNPs) in MUTYH and XRCC1 genes between control group and children with ALL, we have shown that the combined genotypes of examined genes can modulate the risk of childhood ALL in Polish population. We found that the combined genotype Arg/Gln–Cys/Cys of XRCC1/OGG1 (OR 3.83) as well as the Cys/Cys–Tyr/Tyr of OGG1/MUTYH (OR 6.75) increases the risk of ALL. In contrast, the combined genotype Arg/Arg–Ser/Ser of XRCC1/OGG1 (OR 0.40) as well as the Ser/Ser–Tyr/Tyr of OGG1/MUTYH (OR 0.43) played a protective role against this malignant disease. In conclusion, we suggest that polymorphisms of BER genes may be used as an important predictive factor for acute lymphoblastic leukemia in children.     

The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

Background

Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations.

Methodology/Principal Findings

In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016).

Conclusions

Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.     

Association between the Polymorphism rs3217927 of CCND2 and the Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population

CyclinD proteins, the ultimate recipients of mitogenic and oncogenic signals, play a crucial role in cell-cycle regulation. CyclinD2, one of the cyclinD family, is overexpressed in T-acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia and involved in the pathogenesis of leukemias. Recent reports indicated that CCND2 polymorphisms are associated with human cancer risk, thusly we hypothesized that CCND2 gene polymorphisms may contribute to childhood ALL susceptibility. We selected the polymorphism rs3217927 located in the 3′UTR region of CCND2 to assess its associations with childhood ALL risk in a case-control study. A significant difference was found in the genotype distributions of rs3217927 polymorphism between cases and controls (P = 0.019) and homozygous GG genotype may be an increased risk factor for childhood ALL (adjusted OR  =  1.84, 95% CI  =  1.14 —2.99). Furthermore, this increased risk was more pronounced with GG genotype among high-risk ALL (adjusted OR  = 1.95, 95% CI  =  1.04–3.67), low-risk ALL (adjusted OR  =  2.09, 95% CI  =  1.13–3.87), B-phenotype ALL patients (adjusted OR  =  1.78, 95% CI  =  1.08–2.95) and T-phenotype ALL patients (adjusted OR  =  2.87, 95% CI  =  1.16–7.13). Our results provide evidence that CCND2 polymorphism rs3217927 may be involved in the etiology of childhood ALL, and the GG genotype of rs3217927 may modulate the genetic susceptibility to childhood ALL in the Chinese population. Further functional studies and investigations in larger populations should be conducted to validate our findings.     

Polymorphism of genes for xenobiotic metabolism in petrochemical workers

Genetic polymorphism of xenobiotic metabolizing enzymes responsible for individual susceptibility to different environmental factors was examined in a cohort of petrochemical workers occupationally exposed to adverse action of chemical compounds. Molecular genetic analysis of the 1462V mutation in exon 17 of the CYP1A gene demonstrated close similarity between the genotype and allele frequency distribution patterns in the industrial and control groups. No association between the CYP1A polymorphic alleles and genotypes and the duration of service and concomitant diseases was observed. The odds ratio of the disease development in the workers carrying heterozygous CYP1A1 mutant allele was 2.2. Analysis of the STM1 gene polymorphism demonstrated a decrease in the frequency of the homozygous deletion carriers in the workers compared to the control group. There were no substantial differences between the industrial and control groups with respect to the frequencies of rapid and slow acetylator genotypes revealed at the analysis of the NAT2 gene polymorphism. However, considering the concomitant diseases, in the corresponding industrial subgroup a clear trend towards lower frequency of rapid acetylators was demonstrated. In addition, the odds ratio of the disease development for the workers with slow acetylator phenotype was 1.7.     

Thymidylate synthase enhancer region polymorphism not related to susceptibility to acute lymphoblastic leukemia in the Kashmir population

Thymidylate synthase (TS) is a crucial enzyme in folate metabolism and plays a vital role in DNA synthesis and repair. The most common polymorphism in TS is a unique double (2R) or triple (3R) 28-bp tandem repeat sequence in the enhancer region of the TS gene (TSER). This genetic variation in TSER has been widely investigated and has been implicated as a risk factor for the development of various cancers, including acute lymphoblastic leukemia. It has also been found to influence sensitivity to anti-cancer drugs, such as methotrexate. We evaluated this polymorphism in acute lymphoblastic leukemia patients in the Kashmir population. In order to determine whether a double (2R2R) versus a triple (3R3R) 28-bp tandem repeat in the TSER modulates risk for acute lymphoblastic leukemia, 72 acute lymphoblastic leukemia cases and 144 age and gender matched, unrelated healthy individuals from the Kashmir region of India were evaluated for this polymorphism by PCR and direct sequencing. We found the frequency of the TS 2R allele to be 32.6 and 26.0%, in cases and controls, respectively. The TS 2R/2R genotype was found to be present in 15.27% of the cases and 9.72% of the controls, the 2R/3R variant in 34.72% of the cases and 32.63% of the controls, and the 3R/3R genotype in 50.0% of the cases and 57.63% of the controls. There was a significant association between the TS 2R/2R genotype and gender of acute lymphoblastic leukemia patients with males harboring the 2R/2R genotype exhibiting a higher risk of developing acute lymphoblastic leukemia than females (P = 0.009) We concluded that the TSER polymorphism appears not to be a risk factor for susceptibility to acute lymphoblastic leukemia in the Kashmir population.     

Prevalence of GSTT1, GSTM1 and NQO1 (609C>T) in Filipino children with ALL (acute lymphoblastic leukaemia)

In the present paper, we examined the incidence of polymorphic genes involved with the detoxification of exogenous chemicals, including carcinogens, namely GSTT1 (glutathione transferase theta1), GSTM1 (glutathione transferase mu1) and NQO1 (NAD(P)H:quinone oxidoreductase 1) in 60 Filipino paediatric patients with ALL (acute lymphoblastic leukaemia). We found a significantly high incidence of the GSTM1 null genotype in ALL children (71.7%) compared with 51.7% in the control group of children (P<0.05). The GSTT1 null genotype was observed in 35.0% and 33.3% of the ALL cases and the control subjects respectively, with no significant difference. Screening for NQO1 (609C>T) mutant alleles showed a high incidence of the NQO1 C/C genotype (NQO1 homozygous wild-type allele genotype) in 60.0% of ALL cases and was significantly higher than in the control group (23.3%) (P<0.01). These GSTM1 null and NQO1 wild-type genotypes are independently associated with the risk of ALL in Filipino patients. When these two genotypes, GSTM1 null and NQO1 C/C, were combined, the hazard rate for childhood leukaemia was significantly increased (P<0.001). We also noticed that the incidences of GSTM1 null mutations and the NQO1 C/C genotype were significantly higher among Filipinos. These findings suggest a possible role of the GSTM1 null and NQO1 C/C genotypes in the susceptibility of paediatric ALL cases in the Philippines.     

Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl-N-transferase 1 (NAT1), and risk for orofacial clefts

BACKGROUND: Periconceptional supplementation of multivitamins that include folic acid have been shown to prevent several birth defects, including neural tube defects and orofacial clefts. We investigated whether polymorphic variants of fetal acetyl-N-transferase 1 (NAT1), an enzyme involved in the catabolism of folates, differentially interacted with maternal multivitamin use during early pregnancy to alter the risk of delivering an infant with an orofacial cleft malformation. METHODS: Using a large population-based case-control study, we genotyped 421 California infants born with an isolated cleft and 299 controls for two NAT1 polymorphisms. RESULTS: Compared to the homozygous wild-type genotypes, odds ratios for isolated cleft lip with/without cleft palate were slightly increased among infants who were homozygous for the variant alleles of NAT1 1088 and 1095. For isolated cleft palate, no similar associations with these two NAT1 variants were observed. For NAT1 1088 genotypes, we did not observe any differential risks for clefts related to maternal multivitamin intake. For NAT1 1095 genotypes, however, we found a two-fold higher risk for isolated cleft lip with/without cleft palate among infants who were homozygous for the variant allele and whose mothers did not take multivitamins during early pregnancy. CONCLUSIONS: We found evidence suggestive of an interaction between the NAT1 1095 polymorphism and lack of maternal multivitamin use that increased risks of isolated cleft lip with/without cleft palate.     

Influence of GSTT1, mEH, CYP2E1 and RAD51 polymorphisms on diepoxybutane-induced SCE frequency in cultured human lymphocytes

1,3-Butadiene (BD) is a common chemical in the human environment. Diepoxybutane (DEB) is the most reactive epoxide metabolite of BD. The aim of the present study was to evaluate the influence of polymorphisms in enzymes operating in DEB-metabolism (epoxide hydrolase mEH, CYP2E1 and GSTT1), as well as in the DNA-repair enzyme RAD51, on the frequency of sister chromatid exchange (SCE) induced by DEB in lymphocyte cultures from 63 healthy donors. Their genotypes were determined using PCR and restriction fragment length polymorphism (RFLP)-PCR techniques. The analysis of xenobiotic-metabolizing genes revealed that GSTT1 and CYP2E1 polymorphisms have an influence on DEB-induced SCE frequency. Individuals with the GSTT1 null genotype and CYP2E1 c2 variant allele heterozygotes were observed to have significantly higher SCE frequency than individuals with more common genotypes. A correlation between sensitivity to DEB and GSTT1 null genotype indicates that this pathway is a major detoxification step in DEB metabolism in whole-blood lymphocyte cultures, which has been shown in many studies. The analysis of combined polymorphisms indicated that, in the presence of GSTT1, a significantly higher DEB-induced SCE frequency is observed in the CYP2E1 c2 variant allele heterozygotes than in individuals with the most common CYP2E1 genotype. In the absence of GSTT1, however, the CYP2E1 polymorphism has no influence on DEB-induced SCEs. A significant difference was also observed between individuals characterized by low and high mEH activity, but only in subjects with the GSTT1 null genotype. Lack of GSTT1 resulted in higher SCE frequency in individuals with mEH high-activity genotypes than in individuals with mEH low-activity genotype. In the present study no statistically significant difference in DEB-induced SCEs was observed for the RAD51 polymorphism. The influence of GSTT1 genotype on SCE-frequency in RAD51 variant allele carriers was not analysed as all individuals in this group (except one person) had the GSTT1 gene present. Our study shows that the combined analysis of polymorphisms in metabolizing enzymes may lead to a better understanding of their contribution to an individual's susceptibility to DEB.     

Association between polymorphisms of biotransformation and DNA-repair genes and risk of colorectal cancer in Taiwan

The relationship between diet and colorectal cancer has been previously demonstrated and supported with strong epidemiological evidence. The role of genetic polymorphisms has, however, been less well elaborated upon. We conducted a hospital-based case–control study including 727 cases and 736 healthy controls to evaluate the associations of the polymorphic phase-I and -II biotransformations (CYP1A1, CYP1A2, GSTM1, GSTT1, GSTP1, NAT1 and NAT2) and DNA-repair enzymes (XRCC1, XRCC3 and XPD) with the risk of contracting colorectal cancer. We found that men featuring the CYP1A1*2C G/G genotype, the GSTT1 null genotype and XPD 751 with the Gln allele were associated with an elevated risk of colorectal cancer than were men who did not exhibit such genetic features. Multivariate logistic regression analysis revealed that individuals featuring more than two high-risk genotypes increased the colorectal-cancer risk 3.1-fold (OR = 3.1, 95% CI = 1.8–5.2). For women, subjects featuring the CYP1A1*2C G/G genotype and the XRCC3 Thr/Thr genotype faced a 3.1-fold greater risk (95% CI = 1.3–7.0) of colorectal cancer when compared to those featuring the CYP1A1*2C A allele and the XRCC3 Met allele. Taken together, this study suggests that polymorphisms of genes involved in biotransformation and DNA repair could modulate colorectal-cancer risk in Taiwan.     

CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma

Polymorphisms in the selected genes controlling carcinogen metabolism (CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1, GSTT1) considered separately or in different combinations, were investigated for an association with tobacco smoke-associated squamous cell carcinoma (SCC) of the larynx. The case-control study was performed in 289 patients with laryngeal SCC and in 316 cancer-free controls; all were Caucasian males from the same region of Poland and current tobacco smokers. The DNA samples were genotyped using PCR-RFLP and multiplex PCR. The variants' frequencies in both groups were compared; odds ratios and their 95% confidence intervals were calculated by logistic regression analyses. The CYP1A1*1/*4, CYP2D6*4/*4, NAT2*4/*6A genotypes, as well as the CYP1A1*4, CYP2D6*4 and NAT2*4 alleles, were found at significantly higher frequencies in cases than in controls indicating their role as "risk-elevating" factors in laryngeal SCC. Combined genotypes, characterized by the presence of the "risk-elevating" variants at more than one locus, often occurred together with the null variant of the GSTM1 gene and homozygous XPD A/A (Lys751Gln, A35931C) genotype. Furthermore, we identified some "protective" variants, found more frequently in controls than in cases, i.e. the NAT2*6A/*6A and NAT2*5B/*6A genotypes. A distribution of "risk" or "protection" genotypes/alleles seems to be connected with age as an occurrence or risk genes was more frequent in the group of "young" cases (< or = 49 years). Accumulation of certain alleles or genotypes of the CYP1A1, NAT2, GSTM1 and XPD seems to be associated with either increased or decreased risk to develop laryngeal SCC. Therefore, polymorphisms in these genes may play a role in the laryngeal cancer etiology.     

Role of xenobiotic metabolizing gene polymorphisms in breast cancer susceptibility and treatment outcome

Metabolic activation and inactivation of potential genotoxic agents occur by Phase I and Phase II enzymes in multiple interactions. An expanding body of literature demonstrates that ethnic differences in breast cancer incidence may be partly caused by host genetic factors particularly genetic polymorphisms of these carcinogen-metabolizing enzymes. The present case-control study aimed at identification of such low penetrance breast cancer susceptibility genes in 224 Indian women and to investigate the potential effects of their polymorphisms on sporadic breast cancer risk. The main objective of the study was to evaluate the effects of genetic polymorphisms of the xenobiotic metabolizing genes CYP1A1, GSTM1 and GSTT1 on breast cancer risk by PCR-RFLP and DNA sequencing. Our results showed a significant association between CYP1A1 m1, m2 polymorphisms and breast cancer risk; however there was a lack of association between GSTM1 null deletion and breast cancer. The associations of CYP1A1, GSTM1 and GSTT1 genotypes with breast cancer risk were more pronounced among the pre-menopausal patients. Combined genotype analysis revealed the CYP1A1 m2 ValVal-GSTM1 homozygous null deletion genotype combinations to be associated with the highest risk of breast cancer (OR=10.3, 95% CI=1.2-86.1). Correlations with clinicopathological factors and treatment outcome were also analyzed for predicting disease free survival by univariate and multivariate analysis. Significant differences in disease free survival between the wild and polymorphic genotypes were observed only for CYP1A1 m2, GSTT1 genotypes. Our results based on the analysis of functionally relevant polymorphisms in these low penetrance genes may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening and therapeutic intervention in breast cancer. Hence, the present study may provide strong supportive evidence for genetic interactions in the etiology of breast cancer.     

Pharmacogenetic Analysis of Pediatric Patients with Acute Lymphoblastic Leukemia: A Possible Association between Survival Rate and ITPA Polymorphism

Genetic polymorphisms are important factors in the effects and toxicity of chemotherapeutics. To analyze the pharmacogenetic and ethnic differences in chemotherapeutics, major genes implicated in the treatment of acute lymphoblastic leukemia (ALL) were analyzed. Eighteen loci of 16 genes in 100 patients with ALL were analyzed. The distribution of variant alleles were CYP3A4*1B (0%), CYP3A5*3 (0%), GSTM1 (21%), GSTP1 (21%), GSTT1 (16%), MDR1 exon 21 (77%), MDR1 exon 26 (61%), MTHFR 677 (63%), MTHFR 1298 (29%), NR3C1 1088 (0%), RFC1 80 (68%), TPMT combined genotype (7%), VDR intron 8 (11%), VDR FokI (83%), TYMS enhancer repeat (22%) and ITPA 94 (30%). The frequencies of single nucleotide polymorphisms (SNPs) of 10 loci were statistically different from those in Western Caucasians. Dose percents (actual/planned dose) or toxicity of mercaptopurine and methotrexate were not related to any SNPs. Event free survival (EFS) rate was lower in ITPA variants, and ITPA 94 AC/AA variant genotypes were the only independent risk factor for lower EFS in multivariate analysis, which was a different pharmacogenetic implication from Western studies. This study is the first pharmacogenetic study in Korean pediatric ALL. Our result suggests that there are other possible pharmacogenetic factors besides TPMT or ITPA polymorphisms which influence the metabolism of mercaptopurine in Asian populations.