Yongjun Fang

Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population

(Cancer Sci 2010; 101: 782–786)

Association of three polymorphisms in ARID5B, IKZF1and CEBPE with the risk of childhood acute lymphoblastic leukemia in a Chinese population

Recent genome-wide association studies (GWAS) that focus on childhood acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years old, have found evidence that single nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2) and CEBPE (14q11.2) are strongly related to the risk of childhood ALL. These polymorphisms may lead to abnormal expression and dysfunction of the corresponding transcription factors and are likely to increase the risk of ALL. To validate the relationship between these SNPs and the risk of childhood ALL in Chinese population, we conducted a case-control study of 570 ALL cases and 673 controls. We determined that the SNP rs10821936 in ARID5B was statistically significantly associated with the risk of childhood ALL (P<0.0001). The results were also significant for the subgroup analysis of high-risk, medium-risk and low-risk ALL as well as B-lineage ALL. Statistically significant differences were not found in the SNPs for IKZF1 and CEBPE. In conclusion, ARID5B rs10821936 could serve as a potential biomarker for assessing the risk of childhood ALL in Chinese children.

LncRNA NALT interaction with NOTCH1 promoted cell proliferation in pediatric T cell acute lymphoblastic leukemia.

Long non-coding RNA (lncRNA) was referred to be participating in various malignant tumors. Location based analysis of the mechanism in lncRNA and genes have been highly focused. In this study, we reported that lncRNA named NALT which was located near NOTCH1 within 100 bp away. We confirmed that up-regulation of NALT associating with NOTCH1 in human samples. Increased expression of NALT dramatically promoted cell proliferation in cell lines via CCK8 assay and EDU stain. Further xenograft tumor also indicated the growth inducing affection of NALT while could be partial reversed by GSI. Besides, through sorting the side-population cells in T ALL cells treated with NALT shRNA could decrease percentage of SP cell which companied by the down-regulation of NOTCH1. Gal4-λN/BoxB reporter system revealed that the nuclear located NALT could function as a transcription activator which caused an activation of NOTCH signal pathway as confirmed by western blot. Taken together, we found a neighbor of NOTCH1, Lnc-RP11-611D20.2 (named NALT) which could regulate the NOTCH1 signal pathway through cis-regulation. This founding may trigger a comparable development of diagnosis or novel molecularly-directed therapies.

The MIF −173G/C polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population

Migration inhibitory factor (MIF) has recently been defined as a novel pro-tumorigenic factor that promotes cell proliferation, migration, and invasion. The MIF -173C allele results in increased MIF promoter activity and is associated with a higher serum MIF level. We hypothesized that this polymorphism may contribute to childhood acute lymphoblastic leukemia (ALL) susceptibility. We genotyped the MIF -173G/C polymorphism (rs755622) in 346 ALL cases and 516 cancer-free controls in a Chinese population and found that the variant genotype GC and the combined genotypes GC/CC were associated with a significantly higher risk of childhood ALL [adjusted odds ratio (OR)=1.39, 95% confidence interval (CI)=1.01-1.93 for GC and adjusted OR=1.38, 95% CI=1.01-1.89 for GC/CC]. In addition, we found that the increased risk was more pronounced among high-risk ALL and B-phenotype ALL patients. Our results suggest that the MIF -173G/C polymorphism is involved in the etiology of childhood ALL and is a potential candidate gene for determining cancer susceptibility. Further validations in other populations are warranted.

TERT polymorphisms modify the risk of acute lymphoblastic leukemia in Chinese children

Human telomerase reverse transcriptase (TERT) is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. We hypothesized that TERT polymorphisms are associated with risk of childhood acute lymphoblastic leukemia (ALL). We first conducted a case-control study of 570 ALL cases and 673 cancer-free controls of Chinese children, using the tagging single-nucleotide polymorphisms (tSNPs) approach. We then examined the functionality of the important SNPs. We found that TERT promoter region tSNP (rs2735940) and two intron region tSNPs (rs2736100 and rs10069690) were associated with risk of childhood ALL (P = 0.036, 0.011 and 0.022, respectively, in allele comparison). The in vitro luciferase assays in Jurkat cells showed an increased transcriptional activity of rs2735940 T allele compared with the C allele. Additional experiments with ALL bone marrow revealed that the rs2735940 T allele increased levels of the TERT messenger RNA. Notably, TERT intron 2 polymorphism (rs2736100) was associated with lower telomerase activity and longer telomeres. Our findings suggested that TERT promoter rs2735940 polymorphism may affect the TERT activity, and rs2736100 may be associated with telomere function, and thus, it is a potential biomarker for genetic susceptibility to ALL in Chinese children.

Association of genetic variations in mTOR with risk of childhood acute lymphoblastic leukemia in a Chinese population

Abstract The mammalian target of rapamycin (mTOR) is an important protein kinase regulating cell survival and apoptosis. To determine whether genetic variations in mTOR are associated with risk of acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped two tag single nucleotide poymorphisms (SNPs) in mTOR (rs2536 and rs2295080) in a case–control study. We observed that the variant genotype TC of mTOR rs2536 was associated with a significantly decreased risk of childhood ALL (adjusted odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.46–0.96), and the association was more pronounced in high-risk ALL and T-phenotype ALL groups. Additionally, we found that the combined genotypes TC/CC decreased the risk of ALL only in the high-risk ALL group (adjusted OR = 0.54, 95% CI = 0.32–0.91) and T-phenotype ALL group (adjusted OR = 0.29, 95% CI = 0.10–0.84). These results suggest that the mTOR rs2536 polymorphism is involved in the susceptibility to childhood ALL in a Chinese population.

hOGG1 Ser326Cys polymorphism and risk of childhood acute lymphoblastic leukemia in a Chinese population

Oxidative DNA damage caused by reactive oxygen species can produce 8‐oxoguanine (8‐oxoG) in DNA, which is misread and leads to G:C→T:A transversions. This can be carcinogenic. Repair of 8‐oxoG by the base excision repair pathway involves the activity of human 8‐oxoG DNA glycosylase 1 (hOGG1). Accumulating evidence suggests that the hOGG1 Ser326Cys polymorphism affects the activity of hOGG1 and might serve as a genetic marker for susceptibility to several cancers. To determine whether this polymorphism is associated with risk of childhood acute lymphoblastic leukemia (ALL) in Chinese children, we genotyped the hOGG1 Ser326Cys polymorphism (rs1052133) in a case–control study including 415 cases and 511 controls. We found that there was a significant difference in the genotype distributions of the hOGG1 Ser326Cys polymorphism between cases and controls (P = 0.046), and the combined genotypes Ser/Ser and Ser/Cys were associated with a statistically significantly decreased risk of ALL (adjusted odds ratio [OR] = 0.66, 95% confidence interval [CI] = 0.49–0.88, P = 0.005). Furthermore, we found a decreased risk for high risk ALL (adjusted OR = 0.60, 95% CI = 0.40–0.88, P = 0.005), low risk ALL (adjusted OR = 0.68, 95% CI = 0.47–0.99, P = 0.042), and B‐phenotype ALL (adjusted OR = 0.63, 95% CI = 0.46–0.86, P = 0.003) among children with the Ser/Ser and Ser/Cys genotypes. Our results suggest that the hOGG1 Ser326Cys polymorphism is associated with susceptibility to childhood ALL in a Chinese population. (Cancer Sci 2011; 102: 1123–1127)

Hsa-miR-196a2 polymorphism increases the risk of acute lymphoblastic leukemia in Chinese children

Acute lymphoblastic leukemia (ALL) is a major cause of mortality and morbidity in childhood, and the causes of ALL are not completely understood. microRNAs (miRNAs) regulate various biological processes including organ development, cell growth regulation, cell differentiation, apoptosis, and tumorigenesis. We performed a case-control study with 570 childhood ALL cases and 673 cancer-free controls to investigate the association between hsa-miR-196a2 rs11614913 T>C polymorphism and ALL risk. The bioinformatics was used to estimate the potential target of hsa-miR-196a2. In the present study, the hsa-miR-196a2 variant TC heterozygote, and CC/TC genotypes were found to be associated with a significantly increased childhood ALL risk, compared with the TT wild-type homozygote (adjusted OR=1.50, 95% CI=1.15-1.95 for TC and OR=1.40, 95% CI=1.09-1.79 for CC/TC). Further, the difference was pronounced in younger (≤6) subjects or parental non-drinker. The significance of the increased risk is more obvious than the higher treatment branch. Additionally, we found that the rs11614913 TC genotype can increase B-phenotype ALL risk (OR=1.37, 95% CI=1.07-1.76). Finally, combination of three bioinformatics approaches revealed that HOXC8 may be the target gene of hsa-miR-196a2. Taken together, our finding suggested that hsa-miR-196a2 rs11614913 T>C may increase the risk of childhood ALL. Large studies with the function of hsa-miR-196a2 are needed in the further study.

Pri-miR-34b/c rs4938723 polymorphism contributes to acute lymphoblastic leukemia susceptibility in Chinese children

Abstract A polymorphism rs4938723 (T > C) within the promoter region of pri-miR-34b/c has been found to not only affect the expression of mature miR-34b/c but also contribute to the susceptibility to several cancer types. We designed a case-control study to evaluate the role of rs4938723 in childhood acute lymphoblastic leukemia (ALL). The rs4938723 CC genotype was significantly associated with reduced ALL risk (p = 0.003, ORadjusted = 0.51, 95% CI = 0.33–0.80 for CC vs. TT). Stratification analyses showed the differences were pronounced in older (> 6 years), male subjects, as well as in patients in low risk and T-ALL subtypes. The in vitro luciferase assays in Jurkat and K-562 cell lines showed that the transcription activity of miR-34b/c was increased when T allele transited to C allele (p < 0.05). In conclusion, rs4938723 genetic variant contributed to the susceptibility to Chinese childhood ALL by influencing the transcription activity of miR-34b/c promoter.

Methylenetetrahydrofolate reductase gene polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis based on 28 case–control studies

Abstract Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation and nucleotide synthesis. Accumulated evidence has demonstrated that C677T and A1298C polymorphisms of the MTHFR gene are associated with acute lymphoblastic leukemia (ALL) risk, but the results have been inconclusive. To determine a more precise estimation, we performed a meta-analysis of 28 studies with 4240 cases and 9289 controls. We found that the 677TT genotype showed a reduced risk of ALL compared with the 677CC genotype in the overall population (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.61–0.92). The reduced risk was pronounced only among the Caucasian population (OR 0.68, 95% CI 0.51–0.90), not the Asian (OR 0.89, 95% CI 0.75–1.05). For the MTHFR A1298C polymorphism, no significant association with ALL susceptibility was observed in the pooled analyses. However, significantly increased ALL risk was found in childhood inthe comparison of 1298CA versus AA genotype. This study provides evidence that MTHFR polymorphisms may play animportant role in the development of ALL.