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author:("Yu, gongping")
1.  An adjustable fetal weight standard for twins: a statistical modeling study 
BMC Medicine  2015;13:159.
It is a common practice to use a singleton fetal growth standard to assess twin growth. We aim to create a twin fetal weight standard which is also adjustable for race/ethnicity and other factors.
Over half a million twin births of low risk pregnancies in the US, from 1995 to 2004, were used to construct a fetal weight standard. We used the Hadlock’s fetal growth standard and the proportionality principle to make the standard adjustable for other factors such as race/ethnicity. We validated the standard in different race/ethnicities in the US and against previously published curves from around the world.
The adjustable fetal weight standard has an excellent match with the observed birthweight data in non-Hispanic White, non-Hispanic Black, Hispanics, and Asian from 24 to 38 weeks gestation. It also had a very good fit with cross-sectional data from Australia and Norway, and a longitudinal standard from Brazil. However, our model-based 10th and 90th percentiles differed substantially from studies in Japan and US that used the last menstrual period for estimate of gestational age.
The adjustable fetal weight standard for twins is a flexible tool and can be used in different populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0401-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4491250  PMID: 26141190
Adjustable; Fetal; Standard; Twins; Weight
2.  JARID1B promotes metastasis and epithelial-mesenchymal transition via PTEN/AKT signaling in hepatocellular carcinoma cells 
Oncotarget  2015;6(14):12723-12739.
JARID1B is a member of the family of JmjC domain-containing proteins that removes methyl residues from methylated lysine 4 on histone H3 lysine 4 (H3K4). JARID1B has been proposed as an oncogene in many types of tumors; however, its role and underlying mechanisms in hepatocellular carcinoma (HCC) remain unknown. Here we show that JARID1B is elevated in HCC and its expression level is positively correlated with metastasis. In addition Kaplan-Meier survival analysis showed that high expression of JARID1B was associated with decreased overall survival of HCC patients. Overexpression of JARID1B in HCC cells increased proliferation, epithelial-mesenchymal transition, migration and invasion in vitro, and enhanced tumorigenic and metastatic capacities in vivo. In contrast, silencing JARID1B in aggressive and invasive HCC cells inhibited these processes. Mechanistically, we found JARID1B exerts its function through modulation of H3K4me3 at the PTEN gene promoter, which was associated with inactive PTEN transcription. PTEN overexpression blocked JARID1B-driven proliferation, EMT, and metastasis. Our results, for the first time, portray a pivotal role of JARID1B in stimulating metastatic behaviors of HCC cells. Targeting JARID1B may thus be a useful strategy to impede HCC cell invasion and metastasis.
PMCID: PMC4494969  PMID: 25909289
JARID1B; metastasis; epithelial-mesenchymal transition; invasion; PTEN
3.  Paired design study by real-time PCR: miR-378* and miR-145 are potent early diagnostic biomarkers of human colorectal cancer 
BMC Cancer  2015;15:158.
Although microRNAs offer great potential as cancer biomarkers, effective clinical dignostics and tumor maker have not been verified to diagnose with colorectal cancer (CRC). The purpose of our study is to systematically assess the expression of miRNAs in matched cancer and normal tissue samples to identify promising diagnostic microRNA (miRNA) biomarkers for CRC.
In our study, we examined by Real-Time PCR the expression levels of 96 mature miRNA in 32 CRC patients with differently expressed tumors versus normal colon tissues. Using enter and stepwise variable selection methods separately, conditional logistic regression was conducted to identify miRNAs associated with CRC. The classification performance of these indicators was assessed under the Fisher discriminant analysis. Receiver operating characteristic curve analyses were applied to obtain diagnostic utility of the differentially expressed miRNAs.
In this study, we confirmed 11 overexpressed miRNAs with no less than twofold difference, and 85 downexpressed miRNAs with up to 0.5-fold difference in CRC from 96 aberrantly expressed miRNAs being identified by real-time PCR. Conditional logistic regression results confirmed that miRNA-378 and miRNA-145 expression profile was statistically significant. The error diagnosis rate of these two miRNAs are 0.194 and 0.113, separeately, showing by discriminant analysis.
MiRNA-145 and miRNA-378* are potential biomarkers for early detection of CRC, which may help in diagnosing CRC in early period.
PMCID: PMC4436811  PMID: 25896668
MiRNA; Colorectal cancer; Early diagnosis
4.  Polymorphisms in MicroRNA Target Sites of Forkhead Box O Genes Are Associated with Hepatocellular Carcinoma 
PLoS ONE  2015;10(3):e0119210.
The forkhead box O (FOXO) transcription factors play important roles in various cancer development including Hepatocellular Carcinoma (HCC). In this study we conducted a hospital-based case control study including 1049 cases (HCC patients) and 1052 controls (non-tumor patients) to examine whether single nucleotide polymorphisms (SNPs) within microRNA (miRNA) target sites of FOXO genes confer HCC susceptibility. A total of three miRNA target site SNPs in the 3’ untranslated regions (UTR) of FOXO1 (rs17592236), FOXO3 (rs4946936) and FOXO4 (rs4503258) were analyzed. No statistically significant differences were found in genotype distribution for rs17592236, rs4946936, and rs4503258 between the HCC patient group and the tumor-free control group using single factor chi-square analysis (P>0.05). However, multivariate logistic regression analysis showed that the CT/TT genotype in rs17592236 was significantly associated with decreased risk of HCC development (P = 0.010, OR = 0.699, 95% CI: 0.526–0.927) as compared to the CC genotype in rs17592236. Additionally, a genetic interaction was found between rs17592236 and rs4503258 (P = 0.003, OR = 0.755, 95% CI: 0.628–0.908). Functional dual luciferase reporter assays verified that the rs17592236 SNP was a target site of human miRNA miR-137. Together, these results indicate that the rs17592236 polymorphism is associated with decreasing of HCC hereditary susceptibility likely through modulating the binding affinity of miR-137 to the 3’UTR in FOXO1 messenger RNA (mRNA). Further knowledge obtained from this study may provide important evidence for the prevention and targeted therapy of HCC.
PMCID: PMC4357486  PMID: 25739100
5.  Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2012;51(Suppl 1):E132-E141.
Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F1 and E2F2 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped ten selected SNPs in E2F1 and E2F2, including those at the near 5′ UTR, miRNA binding sites at the near 3′ UTR and tagSNPs according to bioinfotmatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e. rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, rs3218123 GT+TT). Compared with those with 0–4 risk genotypes, an increased risk was observed for those who carried 5–8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86–1.26) and 9–10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14–2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 years old), men, non-smokers, non-drinkers, and individuals with family history of cancer first-degree relatives. Additionally, we also observed that those with 5–10 risk genotypes had an earlier SCCHN onset than those with 0–4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis.
PMCID: PMC3370129  PMID: 22344756
E2F1; E2F2; head and neck cancer; polymorphisms; age at onset
6.  DNA Repair Capacity, DNA-Strand Break Repair Gene Polymorphisms, and the Incidence of Hepatocellular Carcinoma in Southwestern Guangxi of China 
DNA and Cell Biology  2012;31(8):1384-1391.
The associations between DNA repair capacity (DRC), DNA repair gene polymorphisms, and the incidence of hepatocellular carcinoma (HCC) have not been determined in high-risk areas. The aims of this study were to investigate whether DRC is related to the incidence of HCC and to determine whether polymorphisms in the DNA repair genes that regulate DRC are associated with the risk of HCC. First, a small case–control study was conducted to examine the association between DRC and the incidence of HCC and the environmental and genetic factors regulating DRC. Then, a large case–control study was conducted to determine whether those DNA repair gene polymorphisms shown to regulate DRC were related to the risk of HCC. The median DRC was significantly lower among the cases (0.80) than the controls (0.93). A multivariate linear regression analysis showed that the HBsAg status (p<0.01), ethnicity (p=0.01), and polymorphisms in the XRCC3-241 (p=0.01) and APE1-148 (p=0.03) gene loci may be impact factors for DRC. In the large case–control study, a stratified analysis showed that individuals with the APE1-148-combined genotype GT+TT likely had a significantly higher HCC risk compared with those with only the GG genotype (crude odds ratio=1.93, 95% confidence interval=1.17–3.17) among the Zhuang ethnicity. However, nonsignificant differences were observed between XRCC3-241 polymorphisms and the HCC risk. DRC may be related to the incidence of HCC as determined by environmental and genetic factors found in southwestern part of the Guangxi Province. Gene–environment interactions play an important role in the incidence and progression of HCC.
Hepatocellular carcinoma is especially prevalent in Asia, with both host genetics and environmental factors ranging from viral infections to toxins contributing to disease induction. In this article, the ability to repair DNA strand breaks is examined.
PMCID: PMC3405453  PMID: 22691054
7.  The miR-184 Binding-Site rs8126 T>C Polymorphism in TNFAIP2 Is Associated with Risk of Gastric Cancer 
PLoS ONE  2013;8(5):e64973.
TNFAIP2 is a crucial gene involved in apoptosis. Single nucleotide polymorphisms (SNPs) in its miRNA binding sites could modulate functions of the miRNA-target genes and thus risk of cancers. In this study, we investigated associations between potentially functional SNPs in the miRNA binding sites of the 3′UTR of TNFAIP2 and gastric cancer risk in a US population.
We conducted a case-control study of 301 gastric cancer patients and 313 cancer-free controls frequency-matched by age, sex and ethnicity. We genotyped four selected TNFAIP2 SNPs (rs8126 T>C, rs710100 G>A, rs1052912 G>A and rs1052823 G>T) and used the logistic regression analysis to assess associations of these SNPs with cancer risk.
The rs8126 CC genotype was associated with a significantly elevated risk of gastric cancer (adjusted OR = 2.00, 95% CI = 1.09–3.64 and P = 0.024), compared with the combined rs8126 TT+TC genotypes, particularly in current drinkers. However, none of other TNFAIP2 SNPs was associated with risk of gastric cancer.
Our data suggested that the TNFAIP2 miRNA binding site rs8126 T>C SNP may be a marker for susceptibility to gastric cancer, and this finding requires further validation by larger studies.
PMCID: PMC3665554  PMID: 23724109
8.  Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx 
Cancer  2011;118(6):1684-1692.
The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN).
Genotyping was conducted on three tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status.
None of three MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers.
The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings.
PMCID: PMC3213304  PMID: 21823114
MDM4 polymorphisms; genetic susceptibility; human papillomavirus; molecular epidemiology; squamous cell carcinoma of head and neck cancer; squamous cell carcinoma of the oropharynx
9.  Polymorphisms of XPG/ERCC5 and risk of squamous cell carcinoma of the head and neck 
Pharmacogenetics and genomics  2012;22(1):50-57.
Xeroderma pigmentosum group G (XPG) protein is essential for the nucleotide excision repair (NER) system, and genetic variations in XPG/ERCC5 that affect DNA repair capacity may contribute to the risk of tobacco-induced cancers, including squamous cell carcinoma of the head and neck (SCCHN). We investigated the association between XPG/ERCC5 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped 12 tagging and potentially functional single nucleotide polymorphisms (SNPs) of XPG/ERCC5 in a case-control study of 1,059 non-Hispanic white patients with SCCHN and 1,066 cancer-free age-and sex matched controls and evaluated their associations with SCCHN risk.
Multivariate logistic regression showed that only an intronic tagging SNP (rs4150351A/C) of XPG/ERCC5 was associated with a decreased risk of SCCHN (adjusted OR=0.76, 95% CI=0.62–0.92 for AC vs. AA; adjusted OR=0.81, 95% CI=0.67–0.98 for AC/CC vs. AA), but this association was nonsignificnant after corrections by the permutation test (empirical P=0.105). In the genotype-phenotype correlation analysis using peripheral lymphocytes from 44 SCCHN patients, we found that rs4150351 AC/CC was associated with a statistically significant increase in XPG/ERCC5 mRNA expression.
These findings suggest that genetic variation in XPG/ERCC5 may not affect the SCCHN risk, although rs4150351 C variant genotypes were associated with the increased expression of XPG/ERCC5 mRNA and nonsignificantly decreased risk of SCCHN. Larger population-based and additional functional studies are warranted to validate our findings.
PMCID: PMC3237901  PMID: 22108238
ERCC5; polymorphism; SCCHN; risk
10.  Association between PARP-1 V762A polymorphism and cancer susceptibility: a meta-analysis 
Genetic epidemiology  2011;36(1):56-65.
Poly(ADP-ribose) polymerase-1 (PARP-1 catalyzes poly(ADP-ribosyl)ation to various proteins involved in many cellular processes, including DNA damage detection and repair, and cell proliferation and death. PARP-1 has been implicated in human carcinogenesis, but the association between the most-studied PARP-1 V762A polymorphism (rs1136410) and risk of various cancers was reported with inconclusive results.
To assess the association between the PARP-1 V762A polymorphism and cancer risk.
A meta-analysis of 21 studies with 12027 cancer patients and 14106 cancer-free controls was conducted to evaluate the strength of the association using odds ratio (OR) with 95% confidence interval (CI).
Overall, no significant association was found between the PARP-1 V762A polymorphism and cancer risk. In the stratified analyses, however, it was found that the variant A allele of the PARP-1 V762A polymorphism was associated with an increased risk of cancer among Asian populations (VA+AA vs.VV: OR = 1.11, 95% CI: 1.01-1.23; Pheterogeneity = 0.210) but a decreased risk of cancer (VA+AA vs.VV: OR =0.89, 95% CI: 0.80-1.00; Pheterogeneity = 0.004), among Caucasian populations, especially for glioma risk (OR = 0.79, 95% CI: 0.69-0.90; Pheterogeneity = 0.800).
This meta-analysis found evidence for an association of the PARP-1 V 762A polymorphism with increased risk of cancer among Asians but decreased risk of cancer among Caucasians, particularly of glioma. Further well designed studies with large sample sizes of different ethnic populations and different cancer types are warranted to confirm these findings.
PMCID: PMC3312993  PMID: 22127734
DNA repair; Case-control study; Meta-analysis; Polymorphism; Susceptibility
11.  Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck 
Molecular carcinogenesis  2011;50(9):697-706.
Both p53 tumor suppressor and murine double minute 2 (MDM2) oncoprotein are crucial in carcinogenesis. We hypothesized that MDM2 promoter single nucleotide polymorphism (SNP)309, A2164G, and p53 codon 72 SNP are associated with risk and age at onset of squamous cell carcinoma of head and neck (SCCHN). We genotyped these SNPs in a study of 1,083 Caucasian SCCHN cases and 1,090 cancer-free controls. Although none of these SNPs individually had a significant effect on risk of SCCHN, nor did their combined putative risk genotypes (i.e. MDM2 SNP309 GT + GG, 2164 AA, and p53 codon 72 CC), we found that individuals with 2–3 risk genotypes had significantly increased risk of non-oropharyngeal cancer (OR = 1.42; 95% CI=1.07–1.88). This increased risk was more pronounced among young subjects, men, smokers, and drinkers. In addition, female patients carrying the MDM2 SNP309 GT and GG genotypes showed a 3-year (56.7 years) and 9-year (51.2 years) earlier age at onset of non-oropharyngeal cancer (Ptrend = 0.007), respectively, compared with those carrying the TT genotype (60.1 years). The youngest age (42.5 years) at onset of non-oropharyngeal cancer was observed in female patients with the combined MDM2 SNP309 GG and p53 codon 72 CC genotypes. The findings suggest that MDM2 SNP309, A2164G, and p53 codon 72 SNPs may collectively contribute to non-oropharyngeal cancer risk and that MDM2 SNP309 individually or in combination with p53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. Further studies with large sample sizes are warranted to validate these results.
PMCID: PMC3142329  PMID: 21656578
squamous cell carcinoma of the head and neck; MDM2; p53; polymorphism; risk; age at onset
12.  Association between Single Nucleotide Polymorphisms in ERCC4 and Risk of Squamous Cell Carcinoma of the Head and Neck 
PLoS ONE  2012;7(7):e41853.
Excision repair cross-complementation group 4 gene (ERCC4/XPF) plays an important role in nucleotide excision repair and participates in removal of DNA interstrand cross-links and DNA double-strand breaks. Single nucleotide polymorphisms (SNPs) in ERCC4 may impact repair capacity and affect cancer susceptibility.
Methodology/Principal Findings
In this case-control study, we evaluated associations of four selected potentially functional SNPs in ERCC4 with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,040 non-Hispanic white patients with SCCHN and 1,046 cancer-free matched controls. We found that the variant GG genotype of rs2276466 was significantly associated with a decreased risk of SCCHN (OR = 0.69, 95% CI 0.50–0.96), and that the variant TT genotype of rs3136038 showed a borderline significant decreased risk with SCCHN (OR = 0.76, 95% CI: 0.58–1.01) in the recessive model. Such protective effects were more evident in oropharyngeal cancer (OR = 0.61, 95% CI: 0.40–0.92 for rs2276466; OR = 0.69, 95% CI: 0.48–0.98 for rs3136038). No significant associations were found for the other two SNPs (rs1800067 and rs1799798). In addition, individuals with the rs2276466 GG or with the rs3136038 TT genotypes had higher levels of ERCC4 mRNA expression than those with the corresponding wild-type genotypes in 90 Epstein-Barr virus-transformed lymphoblastoid cell lines derived from Caucasians.
These results suggest that these two SNPs (rs2276466 and rs3136038) in ERCC4 may be functional and contribute to SCCHN susceptibility. However, our findings need to be replicated in further large epidemiological and functional studies.
PMCID: PMC3407112  PMID: 22848636
13.  Correlation between Base-Excision Repair Gene Polymorphisms and Levels of In-Vitro BPDE–Induced DNA Adducts in Cultured Peripheral Blood Lymphocytes 
PLoS ONE  2012;7(7):e40131.
In vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts in cultured peripheral lymphocytes have been shown to be a phenotypic biomarker of individual’s DNA repair phenotype that is associated with cancer risk. In this study, we explored associations between genotypes of base-excision repair genes (PARP1 Val762Ala, APEX1 Asp148Glu, and XRCC1 Arg399Gln) and in vitro BPDE-induced DNA adducts in cultured peripheral blood lymphocytes in 706 cancer-free non-Hispanic white subjects. We found that levels of BPDE-induced DNA adducts were significantly higher in ever smokers than in never smokers and that individuals with the Glu variant genotypes (i.e., Asp/Glu and Glu/Glu) exhibited lower levels of BPDE-induced DNA adducts than did individuals with the common Asp/Asp homozygous genotype (median RAL levels: 32.0 for Asp/Asp, 27.0 for Asp/Glu, and 17.0 for Glu/Glu, respectively; Ptrend = 0.030). Further stratified analysis showed that compared with individuals with the common APEX1-148 homozygous Asp/Asp genotype, individuals with the APEX1-148Asp/Glu genotype or the Glu/Glu genotype had a lower risk of having higher-level adducts (adjusted OR = 0.60, 95% CI: 0.36–0.98 and adjusted OR = 0.47, 95% CI: 0.26–0.86, respectively; Ptrend = 0.012) among smokers. Such an effect was not observed in non-smokers. However, there was no significant interaction between the APEX1 Asp148Glu polymorphism and smoking exposure in this study population (P = 0.512). Additional genotype-phenotype analysis found that the APEX1-148Glu allele had significantly increased expression of APEX1 mRNA in 270 Epstein-Barr virus-transformed lymphoblastoid cell lines, which is likely associated with more active repair activity. Our findings suggest that the functional APEX1-148Glu allele is associated with reduced risk of having high levels of BPDE-induced DNA adducts mediated with high levels of mRNA expression.
PMCID: PMC3390316  PMID: 22792228
14.  Polymorphisms of MDM4 and risk of squamous cell carcinoma of the head and neck 
Pharmacogenetics and genomics  2011;21(7):388-396.
Mouse double minute 4 (MDM4), a homolog of MDM2, is a key negative regulator of p53, and its amplification or over-expression contributes to carcinogenesis by inhibiting the p53 tumor suppressor activity. We investigated the association between MDM4 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped three MDM4 tagging polymorphisms, two in the 3′ untranslated region (3′ UTR: rs11801299G>A and rs10900598G>T) and one in intron 1 (rs1380576C>G), in a case-control study of 1,075 non-Hispanic white SCCHN patients and 1,084 cancer-free controls and evaluated their associations with SCCHN risk.
Although none of these three polymorphisms individually had a statistically significant effect on risk of SCCHN, nor did their combined number of putative risk genotypes (i.e., rs11801299GG, rs1380576CG+GG, and rs10900598GG) (OR = 1.16 and 95% CI=0.93–1.45), we found that individuals with 1–3 risk genotypes had statistically significantly increased risk of oropharyngeal cancer (OR = 1.32 and 95% CI = 1.00–1.73), particularly for those with T1–2 stage (OR = 1.40; 95% CI = 1.02–1.94), those with regional lymph node metastases (N1–3) (OR = 1.44; 95% CI = 1.07–1.95), and those with late stages (III and IV) (OR = 1.34; 95% CI = 1.01–1.77).
Our results suggest that the joint effect of MDM4 variants may contribute to the risk of oropharyngeal cancer in non-Hispanic whites. Additional studies are warranted to unravel whether the particular stage distribution of oropharyngeal cancer with the strongest association (T1–2, N1–3, and III–IV) is a possible link with human papillomavirus-related oropharyngeal cancers.
PMCID: PMC3116079  PMID: 21540763
MDM4 polymorphism; case-control; genetic susceptibility; molecular epidemiology; head and neck neoplasms; oropharyngeal cancer
15.  An analysis of single nucleotide polymorphisms of 125 DNA repair genes in the Texas genome-wide association study of lung cancer with a replication for the XRCC4 SNPs 
DNA repair  2011;10(4):398-407.
DNA repair genes are important for maintaining genomic stability and limiting carcinogenesis. We analyzed all single nucleotide polymorphisms (SNPs) of 125 DNA repair genes covered by the Illumina HumanHap300 (v1.1) BeadChips in a previously conducted genome-wide association study (GWAS) of 1,154 lung cancer cases and 1,137 controls and replicated the top-hits of XRCC4 SNPs in an independent set of 597 cases and 611 controls in Texas populations. We found that six of 20 XRCC4 SNPs were associated with a decreased risk of lung cancer with a P value of 0.01 or lower in the discovery dataset, of which the most significant SNP was rs10040363 (P for allelic test = 4.89 ×10−4). Moreover, the data in this region allowed us to impute a potentially functional SNP rs2075685 (imputed P for allelic test = 1.3 ×10−3). A luciferase reporter assay demonstrated that the rs2075685G>T change in the XRCC4 promoter increased expression of the gene. In the replication study of rs10040363, rs1478486, rs9293329, and rs2075685, however, only rs10040363 achieved a borderline association with a decreased risk of lung cancer in a dominant model (adjusted OR = 0.80, 95% CI = 0.62–1.03, P = 0.079). In the final combined analysis of both the Texas GWAS discovery and replication datasets, the strength of the association was increased for rs10040363 (adjusted OR = 0.77, 95% CI = 0.66–0.89, Pdominant = 5×10−4 and P for trend = 5×10−4) and rs1478486 (adjusted OR = 0.82, 95% CI = 0.71 −0.94, Pdominant = 6×10−3 and P for trend = 3.5×10−3). Finally, we conducted a meta-analysis of these XRCC4 SNPs with available data from published GWA studies of lung cancer with a total of 12,312 cases and 47,921 controls, in which none of these XRCC4 SNPs was associated with lung cancer risk. It appeared that rs2075685, although associated with increased expression of a reporter gene and lung cancer risk in the Texas populations, did not have an effect on lung cancer risk in other populations. This study underscores the importance of replication using published data in larger populations.
PMCID: PMC3062723  PMID: 21296624
XRCC4; variant; Genetic susceptibility; genome-wide association study; replication study
16.  A Functional NQO1 609C>T Polymorphism and Risk of Gastrointestinal Cancers: A Meta-Analysis 
PLoS ONE  2012;7(1):e30566.
The functional polymorphism (rs1800566) in the NQO1 gene, a 609C>T substitution, leading to proline-to-serine amino-acid and enzyme activity changes, has been implicated in cancer risk, but individually published studies showed inconclusive results.
Methodology/Principal Findings
We performed a meta-analysis of 20 publications with a total of 5,491 cases and 5,917 controls, mainly on gastrointestinal (GI) cancers. We summarized the data on the association between the NQO1 609C>T polymorphism and risk of GI cancers and performed subgroup analyses by ethnicity, cancer site, and study quality. We found that the variant CT heterozygous and CT/TT genotypes of the NQO1 609 C>T polymorphism were associated with a modestly increased risk of GI cancers (CT vs. CC: OR = 1.10, 95% CI = 1.01 – 1.19, Pheterogeneity = 0.27, I2 = 0.15; CT/TT vs. CC: OR = 1.11, 95%CI = 1.02 – 1.20, Pheterogeneity = 0.14; I2 = 0.27). Following further stratified analyses, the increased risk was only observed in subgroups of Caucasians, colorectal cancer in Caucasians, and high quality studies.
This meta-analysis suggests that the NQO1 609T allele is a low-penetrance risk factor for GI cancers. Although the effect on GI cancers may be modified by ethnicity and cancer sites, small sample seizes of the subgroup analyses suggest that further larger studies are needed, especially for non-colorectal GI cancers in Caucasians and GI cancers in Asians.
PMCID: PMC3260285  PMID: 22272361
17.  Clinicopathological significance of RASSF1A reduced expression and hypermethylation in hepatocellular carcinoma 
Hepatology International  2010;4(1):423-432.
Protein downregulation and hypermethylation of Ras association domain family 1A (RASSF1A) has been recognized as an important early event in different classes of carcinogenesis, but clinicopathological significance of RASSF1A protein expression and methylation in hepatocellular carcinoma (HCC) remains largely unknown. The aim of the study was to investigate the expression of RASSF1A protein and methylation in HCC and their clinical significance.
Immunohistochemistry was employed to detect the expression of RASSF1A proteins in liver tissue microarrays. Aberrant promoter hypermethylation of RASSF1A was investigated in DNA from HCC, matching noncancerous tissues and serum of 35 HCC patients by methylation-specific PCR.
RASSF1A protein expression in HCC was significantly lower than that in noncancerous (p = 0.015) and paracancerous tissues (p = 0.017). In addition, reduced RASSF1A protein expression is related to TNM stage, metastasis, α-fetoprotein, portal vein embolus, capsular infiltration, and multiple tumor nodes. Furthermore, RASSF1A promoter methylation in HCC was significantly higher than that in noncancerous liver tissues (p < 0.05). Meanwhile, RASSF1A promoter hypermethylation was detected in 14 in the serum DNA from HCC patients, whereas no hypermethylation was detected in the normal controls. Hypermethylation of RASSF1A in HCC serum and tissues was negatively correlated with the expression of RASSF1A protein expression (p < 0.05).
The loss or abnormal protein downregulation and the promoter hypermethylation of RASSF1A could play important roles in the tumorigenesis development and metastases of HCC. The detection of the promoter hypermethylation of RASSF1A in serum DNA could be a valuable biomarker for early-stage diagnosis in populations at high risk of HCC.
PMCID: PMC2836437  PMID: 20305761
RASSF1A; Hepatocellular carcinoma; Immunohistochemistry; Promoter hypermethylation; Tissue microarrays (TMAs); DNA

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