FOXO3 gene polymorphisms influence the risk of acute lymphoblastic leukemia in Chinese children

Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed cancer in children and single-nucleotide polymorphisms (SNPs) in certain genes influence risk of ALL. Although FOXO3 had been demonstrated to be involved leukemia, the role of FOXO3 polymorphisms was still not clear. In the present study, we explored the association of FOXO3 SNPs with ALL risk in Chinese children. We genotyped four polymorphisms (rs17069665 A>G, rs4945816 T>C, rs4946936 C>T, and rs9400241 A>C) of FOXO3 in 425 ALL cases and 1339 health controls. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Further analyses were performed to explore associations of rs17069665 and rs9400241 with ALL susceptibility in terms of age, gender, immunophenotype, minimal residual disease (MRD), and other clinical characteristics. We found rs17069665 related to the increased ALL risk (OR = 1.76; 95% CI = 1.02-3.04), rs9400241 related to decreased ALL risk (OR = 0.80; 95% CI = 0.64-0.99). The effects of rs17069665 on ALL risk were more predominant in males and children < 10 years, and patients with lower rates of platelet or neutrophil. As for rs9400241, the effects were more predominant in children < 10 years, and in patients with pre B ALL, positive MRD, anemia, or hepatomegaly. In conclusion, FOXO3 gene polymorphisms influence the risk of ALL in children and might be a potential biomarker for ALL susceptibility.     

CXCL12 and TP53 genetic polymorphisms as markers of susceptibility in a Brazilian children population with acute lymphoblastic leukemia (ALL)

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Genetic polymorphisms in the 3′UTR region of the CXCL12 (rs1801157) and TP53 codon 72 (rs1042522) genes may contribute to susceptibility to childhood ALL because they affect some important processes, such as metastasis regulation and tumor suppression. Thus the objective of the present study was to detect the frequency of two genetic polymorphisms in ALL patients and controls and to add information their impact on genetic susceptibility and prognosis. The CXCL12 and TP53 polymorphisms were tested in 54 ALL child patients and in 58 controls by restriction fragment length polymerase chain reaction and allelic specific chain reaction techniques, respectively. The frequencies of both allelic variants were higher in ALL patients than in the controls and indicated a positive association: OR = 2.44; 95 % CI 1.05–5.64 for CXCL12 and OR = 2.20; 95 % CI 1.03–4.70 for TP53. Furthermore, when the two genetic variants were analyzed together, they increased significantly more than fivefold the risk of this neoplasia development (OR = 5.24; 95 % CI 1.39–19.75), indicating their potential as susceptibility markers for ALL disease and the relevance of the allelic variant combination to increased risk of developing malignant tumors. Future studies may indicate a larger panel of genes involved in susceptibility of childhood ALL and other hematological neoplasias.     

Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia

Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2′-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.     

Association between the TP53 polymorphisms and lung cancer risk: a meta-analysis

The previous published data on the association between TP53 codon 72, intron 6, and intron 3 16 bp polymorphisms and lung cancer risk remained controversial. This meta-analysis of literatures was performed to derive a more precise estimation of the relationship. 38 publications with 51 studies were selected for this meta-analysis, including 17,337 cases and 16,127 controls for TP53 codon 72 (from 43 studies), 2,201 cases and 2,399 controls for TP53 intron 6 (from four studies), and 4,322 cases and 4,558 controls for TP53 intron 3 16 bp (from four studies). When all the eligible studies were pooled into the meta-analysis of codon 72 polymorphism, there was significant association between lung cancer risk and codon 72 polymorphism in any genetic model (dominant model: OR = 1.13, 95 % CI 1.05–1.21; recessive model: OR = 1.14, 95 % CI 1.02–1.27; additive model: OR = 1.19, 95 % CI 1.05–1.33). In the subgroup analysis by ethnicity, histological type, source of control, and smoking status, significantly increased risks were observed in subgroups such as Asians, Caucasians, lung squamous cell carcinoma patients for Asians, population-based study, hospital-based study, non-smokers, and smokers. When all the eligible studies were pooled into the meta-analysis of intron 6 polymorphism, there was significant association between lung cancer risk and intron 6 polymorphism in dominant model (OR = 1.27, 95 % CI 1.11–1.44). When all the eligible studies were pooled into the meta-analysis of intron 3 16 bp polymorphism, there was significant association between lung cancer risk and intron 3 16 bp polymorphism in dominant model (OR = 1.12, 95 % CI 1.02–1.23) and additive model (OR = 1.41, 95 % CI 1.04–1.90). Additionally, when one study was deleted in the sensitive analysis, the results of TP53 intron 3 16 bp duplication polymorphism were changed in the dominant model (OR = 1.11, 95 % CI 0.87–1.42) and additive model (OR = 1.01, 95 % CI 0.65–1.56). In summary, this meta-analysis indicates that codon 72 and intron 6 polymorphisms show an increased lung cancer risk. A study with the larger sample size is needed to further evaluated gene-environment interaction on TP53 codon 72, intron 6, and intron 3 16 bp polymorphisms and lung cancer risk.     

Association of TP53 codon 72 and CDH1 genetic polymorphisms with colorectal cancer risk in Bangladeshi population

Till now no pharmacogenetic study of TP53 codon 72 (Arg72Pro) and CDH1 rs16260 (-160C<A) genes has been reported on Bangladeshi population relating those with colorectal cancer. So the aim of the study is to determine whether there is an elevated risk of colorectal cancer development with TP53 codon 72 and CDH1 rs16260 genetic polymorphism in Bangladeshi population for the first time. To investigate the association of these two SNPs, we conducted a case-control study with 288 colorectal cancer patients and 295 healthy volunteers by using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. We found an increased risk of association between Arg/Pro heterozygosity (adjusted OR = 2.58, 95% CI = 1.77–3.77, p < 0.05) and Pro/Pro mutant homozygosity (adjusted OR = 2.92, 95% CI = 1.78–4.78, p < 0.05) along with the combined genotype (Arg/Pro + Pro/Pro) (adjusted OR = 2.70, 95% CI = 1.90–3.82, p < 0.05) and colorectal cancer predisposition. In case of CDH1 rs16260 polymorphism, C/A heterozygous and A/A mutant homozygous are significantly (p < 0.05) found to be associated with colorectal cancer risk with adjusted OR of 1.94 and 2.63, respectively. The combined genotype of C/A and A/A was also found to be strongly associated with colorectal cancer risk compared to C/C genotype (adjusted OR = 2.02, 95% CI = 1.42–2.87, p < 0.05). In conclusion, heterozygosity and mutant homozygosity as well as the combination of both TP53 Arg72Pro and CDH1 rs16260 polymorphisms are responsible to increase the risk of colorectal cancer development in Bangladeshi population.     

CYP3A5 and NAT2 gene polymorphisms: role in childhood acute lymphoblastic leukemia risk and treatment outcome

Susceptibility to acute lymphoblastic leukemia can be highly influenced by genetic polymorphisms in metabolizing enzyme genes of environmental carcinogens. This study aimed to evaluate the impact of the CYP3A5 and NAT2 metabolizing enzyme polymorphisms on the risk of childhood acute lymphoblastic leukemia. The analysis was conducted on 204 ALL patients and in 364 controls from a Brazilian population, using PCR-RFLP. The CYP3A5 3 polymorphic homozygous genotype was more frequent among ALL patients and the 3 allele variant was significantly associated with increased risk of childhood ALL (OR = 0.29; 95% CI, 0.14-0.60). The homozygous polymorphic genotype for the 6 allele variant was extremely rare and found in only two individuals. The heterozygous frequencies were similar for the ALL group and the control group. No significant differences were observed between the groups analyzed regarding NAT2 variant polymorphisms. None of the polymorphisms analyzed was related to treatment outcome. The results suggest that CYP3A5 3 polymorphism may play an important role in the risk of childhood ALL.     

Serum copper investigations in children with acute lymphoblastic leukemia.

Serum copper level (SCL) was studied in 57 children with acute lymphoblastic leukemia (ALL) by atomic absorption spectrophotometry. It was found that changes in serum copper are to a greater extent related to the clinical course of ALL than to the age of the children examined. The highest mean SCL were obtained in untreated patients (261.2 microgram/100ml). Normalization of myelograms during treatment is accompanied by decrease of SCL. The significant increase of SCL in comparison with SCL in remission (129.8 microgram/100ml) occurred in extramarrow localizations (163.8 microgram/100 ml) and in the group of cases where after 1/2...2 months of maintenance therapy the recurrence of ALL was noted (168.8 microgram/100 ml). These observations suggest that SCL estimation may be useful as a auxiliary test in the clinical evaluation of the disease, for efficiacy of therapy and in predicting recurrences of ALL.     

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.     

Association of interleukin-10 gene promoter polymorphisms with susceptibility to acute pyelonephritis in children

Interleukin-10 (IL-10) is a potent inhibitor of leukocyte chemotaxis, bacterial killing in phagocytes and synthesis of pro-inflammatory cytokines and chemokines, and recent studies have suggested an important role for this immunoregulatory cytokine in the pathogenesis of urinary tract infections (UTIs). Therefore, the gene encoding IL-10 (IL10) is an attractive candidate for association studies attempting to identify susceptibility genes conferring risk of UTIs. In this case–control study, we aimed to investigate the association of single nucleotide polymorphisms (SNPs) in the promoter region of IL10 with acute pyelonephritis in the Slovak population. Polymerase chain reaction with sequence-specific primers was used to analyse IL10 ?1082A/G (rs1800896), ?819C/T (rs1800871) and ?592C/A (rs1800872) SNPs in 147 children with acute pyelonephritis and 215 healthy controls. Comparison of patients with healthy controls using the logistic regression analysis revealed significantly increased risk of developing recurrent attacks of acute pyelonephritis for ?1082 G allele in a dominant genetic model GG (GG + AG vs. AA, P?=?0.019, odds ratio (OR)?=?2.26). A similar tendency was also found when the recurrent acute pyelonephritis subgroup was compared to episodic pyelonephritis cases (GG + AG vs. AA, P?=?0.009, OR?=?3.38). In conclusion, our results suggest that IL10 ?1082 A/G SNP is a susceptibility factor for development of recurrent attacks of acute pyelonephritis.     

Compression fractures of the vertebrae in children with acute lymphoblastic leukemia]

Compression fractures of vertebrae were noted in 20 out of 1,700 children with the acute lymphoblastic leukemia. Usually prognosis in these cases has been favourable (70% of patients are alive from 5 months to 19 years). Percentage of recovery from compression fractures has been relatively high. Lymphoblastic leukemia with infiltrations localized in the spine is relatively non-aggressive, develops slowly, and despite extensive lesions to the bones its outcome results are favourable. Main symptom of spinal involvement include severe and persisting back aches which make walking impossible. Such symptoms should indicate the diagnosis of leukemia and advocate proper hematological examinations.     

Association of TP53 gene codon 72 polymorphism with endometriosis in Mexican women

The TP53 tumor suppressor gene plays an important role in cell cycle regulation; polymorphisms of this gene have been associated with endometriosis. We examined the role of TP53 codon 72 polymorphism by comparing genotypes of 235 healthy Mexican women (controls with surgically excluded endometriosis) with the genotypes of 151 Mexican women with endometriosis. The observed genotype frequencies for controls and endometriosis patients were 8 and 22% for proline/proline (Pro/Pro), 30 and 34% for proline/arginine (Pro/Arg), and 62 and 44% for arginine/arginine (Arg/Arg), respectively. We found that odds ratio (OR) = 3.3; 95% confidence intervals (95%CI) = 1.7-6.4; P = 0.0001. The association was also evident in the comparison of the distributions of genotypes Pro/Pro and Pro/Arg in patients with moderate-to-severe endometriosis; OR = 1.9; 95%CI = 0.95-3.9; P = 0.049. We suggest that genotype Pro/Pro of codon 72 polymorphism in TP53 contributes significantly to endometriosis susceptibility in the Mexican population.     

Changes of CSF-Cu and -Zn in children with acute lymphoblastic leukemia

In 20 Dutch children with acute lymphoblastic leukemia (ALL), Cu and Zn levels in cerebrospinal fluid (CSF) were studied during standard treatment (Protocol ALL-BFM-86/SNWLK-ALL-VII). CSF-Cu in 10 controls was 0.04±0.02 μmol/L, lower compared to values in adults. At the moment of diagnosis, CSF-Cu values were higher, 0.06±0.03 μmol/L, and during maintenance therapy lower, 0.01±0.01 μmol/L. Children with central nervous system (CNS) involvement ALL as judged by CAT Scan and EEG—in addition to cytology—showed lower CSF-Cu values compared to children without. CSF-Zn values were also measured. CSF-Zn was 0.05 μmol/L and did not vary. Cu/Zn molar ratios were increased at the onset of treatment, and decreased during maintenance therapy. The changes in CSF-Cu may follow the natural course of the disease or may relate to the success of treatment, reflecting a decrease of leukemia activity. Another explanation concerns a risk to CNS damage by low CSF-Cu causing neuron dysfunction. Conditions necessary for the interpretation of these results into a clinical strategy for followup study are outlined.     

The role of interleukin-15 polymorphisms in adult acute lymphoblastic leukemia

Background

Interleukin-15 (IL-15) plays important roles in the immune system and in the development of hematopoietic cells. Previous studies revealed that five SNPs in IL-15, rs10519612, rs10519613, rs35964658, rs17007695 and rs17015014, were significantly associated with childhood Acute Lymphoblastic Leukemia (ALL) treatment response. In adult ALL, the expression of IL-15 was also correlated with the immunophenotypes of ALL. Therefore, we hypothesize that SNPs of IL-15 might also be associated with adult ALL.

Methods and Findings

We genotyped the above five SNPs of IL-15 gene by PCR-RFLP assays in adult ALL case-control studies. The current study included 121 adult ALL patients and 263 healthy controls. IL-15 genotypes and haplotypes were determined and the associations with the risk of ALL were analyzed by logistic regression. SNPs rs10519612 and rs17007695 were significantly associated with ALL (P = 0.013 and P = 0.001). We observed a 2-fold and 2.4-fold excess risk of developing ALL for the rs10519612 CC and rs17007695 TC genotype carriers compared with non-carriers, respectively. Haplotype analysis revealed that haplotypes ACAC, CAGT and CCAT were significantly associated with adult B-ALL, while haplotype CCAT conferred susceptibility to T-ALL.

Conclusion

These findings suggest that IL-15 gene polymorphisms are significantly associated with ALL in adult Chinese population.     

Overweight as a prognostic factor in children with acute lymphoblastic leukemia

Our purpose was to investigate the prognostic impact of overweight/obesity in 5-year event-free survival (EFS) in a cohort of children with acute lymphoblastic leukemia (ALL). We retrospectively analyzed 181 newly diagnosed ALL children enrolled between 1990 and 2009 and treated with Berlin-Frankfurt-Munich (BFM) protocols. The majority of children in our cohort were <10 years-old. Our data clearly indicated that overweight/obesity is an independent predictor of relapse risk, mainly in the intermediate- and high-risk groups (HR) of children. These results could be explained by changes in the chemotherapy pharmacokinetics in overweight/obese patients and by the antiapoptotic effects in leukemic cells caused by adipocytes.     

Acute pancreatitis during L-asparaginase treatment in children with acute lymphoblastic leukemia

L-asparaginase (L-ASPA) has been put to a wide application in many therapeutic protocols, above all in the treatment of acute lymphoblastic leukemia (ALL). We presented three cases of acute pancreatitis in children with ALL induced by administration of L-ASPA preparations. Our observations revealed that ultrasound investigations are very useful in diagnosis and monitoring changes in the pancreas. The use of L-ASPA derivatives allows to decrease the toxic and allergic sequele resulting from the administration of the drug.     

Factors contributing to the impairment of growth in children with acute lymphoblastic leukemia

Growth was studied in 88 long-term survivors of acute lymphoblastic leukemia who had been treated with three different regimens of therapy. The following time periods were evaluated: (1) during therapy; (2) between the end of therapy and the onset of puberty, and (3) between the onset of puberty and the most recent observation. We found: (1) a reduction of height SDS during therapy, related to the irradiation dose used; no significant effect of the duration of the therapy could be established; (2) a normal growth rate during the second time period studied for the total group, but a further decrease in height SDS for those found to be growth hormone deficient after therapy (47%), and (3) a further decrease in height SDS during puberty. The timing of puberty in the female patients was normal. We conclude that in patients treated for acute lymphoblastic leukemia, growth impairment has several components, different in timing and mechanism.