Yao Xue

Genetic variants in lncRNA HOTAIR are associated with risk of colorectal cancer

Long non-coding RNA HOX transcript antisenseRNA (HOTAIR) has been widely identified to participate in tumour pathogenesis, acting as a promoter in colorectal cancer carcinogenesis. However, the association between genetic variants in HOTAIR and cancer risk has not yet been reported. In the present study, we performed a two-stage case-control study to investigate the association between HOTAIR tagSNPs and the risk of colorectal cancer. We found that individuals with rs7958904 CC genotype had a significantly decreased risk of colorectal cancer in both Stage 1 and 2, compared with those carrying GG genotype [odds ratio (OR) = 0.70, 95% confidence interval (CI) = 0.51-0.97 in Stage 1; OR = 0.58, 95% CI = 0.37-0.91 in Stage 2; OR = 0.67, 95% CI = 0.51-0.87 in combined stage]. The subsequently stratified analyses showed that the protective effect of rs7958904 was more pronounced in several subgroups. In summary, our study showed that genetic variants in HOTAIR were associated with risk of colorectal cancer and rs7958904 may act as a potential biomarker for predicting the risk of colorectal cancer.

Genome-wide analysis of long noncoding RNA signature in human colorectal cancer.

Long noncoding RNAs (lncRNAs) have been widely regarded as crucial regulators in various biological processes involved in carcinogenesis. However, the comprehensive lncRNA expression signature in colorectal cancer remains fully unknown. We performed a high throughput microarray assay to detect lncRNA expression profile in three paired human colorectal cancer tissues and their adjacent normal tissues. Additional 90 paired colorectal samples were collected to verify differently expression levels of two selected lncRNAs using q-RT-PCR assay. Bioinformatic approaches were performed to explore into the functions of these differently expressed lncRNAs. Microarray assay showed a series of lncRNAs were differently expressed in colorectal cancer. Two of the lncRNAs, HOTAIR and a novel lncRNA, lncRNA-422 were confirmed in more samples (P=0.015 for HOTAIR and P=0.027 for lncRNA-422, respectively). GSEA indicated that gene sets most correlated with them were those named up-regulated in KRAS-over, down-regulated in JAK2-knockout, down-regulated in PDGF-over and down-regulated in TBK1-knockout, all of which were cancer-related. Subsequently, GO analyses of most significantly correlated coding genes of HOTAIR and lncRNA-422 showed that these two lncRNAs may participate in carcinogenesis by regulating protein coding genes involved in special biological process relevant to cancer. Our study demonstrated that different lncRNA expression patterns were involved in colorectal cancer. Besides, HOTAIR and lncRNA-422 were identified to participate in colorectal cancer. Further studies into biological mechanisms of differently expressed lncRNAs identified in our study will help to provide new perspective in colorectal cancer pathogenesis.

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.

Intron 3 Sixteen Base Pairs Duplication Polymorphism of P53 Contributes to Breast Cancer Susceptibility: Evidence from Meta-Analysis

Background P53 is a tumor suppressor gene and plays important role in the etiology of breast cancer. Intron 3 sixteen-bp duplication polymorphism of p53 has been reported to be associated with breast cancer risk. However, the reported results remain conflicting rather than conclusive. Methods A meta-analysis including 19 case-control studies was performed to address this issue. Odds ratios (ORs) with 95% confidence intervals (CIs) were adopted to evaluate the association. Results The overall results suggested that the variant genotypes were associated with a significantly increased breast cancer risk (Del/Ins vs Del/Del: OR = 1.18, 95% CI: 1.00–1.40; Ins/Ins vs Del/Del: OR = 1.42, 95% CI = 1.09–1.84; Ins/Ins+Del/Ins vs Del/Del: OR = 1.21, 95% CI = 1.03–1.41). When stratifying by sample size of studies, a significantly elevated risk was also observed among large sample studies (>500 subjects) but not among small sample studies (≤500 subjects). Conclusion These results suggested that the 16-bp duplication polymorphism of p53 may contribute to susceptibility to breast cancer. Additional well-designed large studies were required to validate this association in different populations.

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)

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.

ADH1C Ile350Val polymorphism and cancer risk: evidence from 35 case-control studies.

Background Alcohol dehydrogenase 1C (ADH1C) is the key enzyme catalyze oxidation of alcohol to acetaldehyde, which plays vital roles in the etiology of various cancer. To date, studies investigated the association between a functional polymorphism in ADH1C, Ile350Val (rs698), and risk of cancer have shown inclusive results. Methods A meta-analysis based on 35 case-control studies was performed to address this issue. Odds ratios (OR) with 95% confidence intervals (CIs) were used to assess the association. The statistical heterogeneity across studies was examined with χ2-based Q-test. Results Overall, no significant associations between ADH1C Ile350Val polymorphism and cancer risk were observed in any genetic models (P>0.05). In the stratified analyses, there was a significantly increased cancer risk among African (Val/Val vs. Ile/Ile OR  = 2.19, 95% CI  = 1.29−3.73, P heterogeneity  = 0.989; Ile/Val + Val/Val vs. Ile/Ile: OR  = 1.79, 95%CI  = 1.18−2.71, P heterogeneity  = 0.761; Val/Val vs. Ile/Val + Ile/Ile: OR  = 1.92, 95% CI  = 1.16−3.17, P heterogeneity  = 0.981) and Asian (Ile/Val vs. Ile/Ile: OR  = 1.58, 95% CI  = 1.32−1.90, P heterogeneity  = 0.375; Val/Val vs. Ile/Ile: OR  = 3.84, 95% CI  = 1.74−8.49, P heterogeneity  = 0.160; Ile/Val + Val/Val vs. Ile/Ile: OR  = 1.65, 95% CI  = 1.38−1.96, P heterogeneity  = 0.330; Val/Val vs. Ile/Val + Ile/Ile: OR  = 3.54, 95% CI  = 1.62−7.75, P heterogeneity  = 0.154) studies. Conclusions The results indicate that ADH1C Ile350Val polymorphism may contribute to cancer risk among Africans and Asians. Additional comprehensive system analyses are required to validate this association combined with other related polymorphisms.

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.