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1.  Association of leukocyte mitochondrial DNA content with glioma risk: evidence from a Chinese case–control study 
BMC Cancer  2014;14(1):680.
Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) content may be implicated in the tumorigenesis of several malignancies. However, the association between mtDNA content in peripheral blood lymphocytes (PBLs) and glioma risk has not been investigated.
Real-time PCR was used to examine the mtDNA content in PBLs of 414 glioma patients and 414 matched controls in a hospital-based case–control study. The association between mtDNA content and glioma risk was evaluated using an unconditional multivariate logistic regression model.
We found that glioma patients exhibited a significantly higher median mtDNA content than healthy controls (0.99 vs. 0.71, P < 0.001). Unconditional multivariate logistic regression analysis adjusting for age, gender, smoking status, and family cancer history showed that there was an S-shaped association between mtDNA content and glioma risk. Higher mtDNA content was significantly associated with an elevated risk of glioma. Compared with the first quartile, the odds ratio (95% confidence interval) for subjects in the second, third, and fourth quartiles of mtDNA content were 0.90 (0.52-1.53), 3.38 (2.15-5.31), and 5.81 (3.74-9.03), respectively (P for nonlinearity = 0.009). Stratified analysis showed that the association between mtDNA content and glioma risk was not modulated by major host characteristics.
Our findings demonstrate for the first time that a higher mtDNA content in PBLs is associated with an elevated risk of glioma, which warrants further investigation in larger populations.
PMCID: PMC4177174  PMID: 25234800
Case–control study; Mitochondrial DNA content; Peripheral blood leukocyte; Real-time PCR; Glioma risk
2.  Postoperative hyperphosphatemia significantly associates with adverse survival in colorectal cancer patients 
Hyperphosphatemia has been implicated in the development and treatment of various cancers. However, whether it can be used as a direct prognostic marker of colorectal cancer (CRC) has remained unexplored. Given new insights into the importance of hyperphosphatemia in CRC, we sought to evaluate the association of hyperphosphatemia with the clinical outcomes of this disease.
In a retrospective analysis of a well-characterized clinic-based cohort with 1,241 CRC patients, we assessed the association of postoperative hyperphosphatemia with patient overall survival.
Postoperative hyperphosphatemia measured within the first month after surgery was significantly associated with CRC survival. Compared to patients with a normal phosphate level, those with hyperphosphatemia exhibited a significant unfavorable overall survival with a hazard ratio (HR) of 1.84 (95% confidence interval [CI] 1.49–2.29, P=2.6×10−8, (log-rank P=1.2×10−7). Stratified analyses indicated the association was more pronounced in patients with colon (HR=2.00, 95% CI 1.57–2.56, P=3.17×10−8) but not rectal cancer (HR=0.96, 95% CI 0.58–1.59, P=0.889) (P interaction=0.023), as well as in those not receiving chemotherapy (HR=2.15, 95% CI 1.59–2.90, P=6.2×10−7) but not in those receiving chemotherapy (HR=1.30, 95% CI 0.92–1.82, P=0.136) (P interaction=0.012). Flexible parametric survival model demonstrated that the increased risk for death conferred by postoperative hyperphosphatemia persisted over 150 months after surgery.
Our data indicated that postoperative hyperphosphatemia might be used as a prognostic marker of CRC patients after surgery. Since phosphate level is routinely tested in clinics, it may be incorporated into clinical models to predict CRC survival.
PMCID: PMC3775915  PMID: 23611210
phosphate; hyperphosphatemia; CRC; survival
3.  Predictive value of alpha-fetoprotein in the long-term risk of developing hepatocellular carcinoma in patients with hepatitis B virus infection – Results from a clinic-based longitudinal cohort 
Although serum level of alpha-fetoprotein (AFP) has long been used to complement imaging tests in the screening and diagnosis of hepatocellular carcinoma (HCC), whether it can be used as a predictive marker of long-term risk for developing HCC in patients with hepatitis B virus (HBV) has not been extensively evaluated and thus remains controversial.
We retrospectively conducted a clinic-based longitudinal cohort study including 617 Korean American patients with HBV who had been followed for up to 22 years (median follow-up time, 6.2 years) to evaluate the association between baseline serum AFP level and the long-term risk of HCC.
The median baseline AFP value of these patients was 3.8 ng/ml. Compared to patients with lower-than-median AFP value, those with higher-than-median baseline serum AFP had a significantly increased risk of developing HCC with an hazard ratio (HR) of 2.73 (95% confidence interval [CI] 1.25–5.99), independent of other major HCC risk factors. In addition, we calculated the cumulative incidence of HCC during different years of follow-up time by baseline serum AFP, and found that the cumulative incidence of HCC was significantly higher in HBV patients with high baseline serum AFP compared to those with low baseline serum AFP in each of the five follow-up time periods examined.
Our results indicated that AFP was a strong independent prospective predictor of long-term HCC risk in high-risk HBV patients. More targeted prevention and early detection of HCC may be considered for these patients.
PMCID: PMC3382017  PMID: 22436980
Alpha-fetoprotein (AFP); hepatitis B virus (HBV); hepatocellular carcinoma (HCC)
4.  Preoperative Platelet Count Associates with Survival and Distant Metastasis in Surgically Resected Colorectal Cancer Patients 
Platelets have been implicated in cancer metastasis and prognosis. No population-based study has been reported as to whether preoperative platelet count directly predicts metastatic recurrence of colorectal cancer (CRC) patients.
Using a well-characterized cohort of 1,513 surgically resected CRC patients, we assessed the predictive roles of preoperative platelet count in overall survival, overall recurrence, as well as locoregional and distant metastatic recurrences.
Patients with clinically high platelet count (≥400× 109/L) measured within 1 month before surgery had a significantly unfavorable survival (hazard ratio [HR]=1.66, 95 % confidence interval [CI] 1.34–2.05, P=2.6×10−6, Plog rank= 1.1×10−11) and recurrence (HR=1.90, 1.24–2.93, P=0.003, Plog rank=0.003). The association of platelet count with recurrence was evident only in patients with metastatic (HR=2.81, 1.67–4.74, P=1.1×10−4, Plog rank =2.6×10−6) but not locoregional recurrence (HR=0.59, 95 % CI 0.21–1.68, P= 0.325, Plog rank=0.152). The findings were internally validated through bootstrap resampling (P<0.01 at 98.6 % of resampling). Consistently, platelet count was significantly higher in deceased than living patients (P<0.0001) and in patients with metastatic recurrence than locoregional (P= 0.004) or nonrecurrent patients (P<0.0001). Time-dependent modeling indicated that the increased risks for death and metastasis associated with elevated preoperative platelet counts persisted up to 5 years after surgery.
Our data demonstrated that clinically high level of preoperative platelets was an independent predictor of CRC survival and metastasis. As an important component of the routinely tested complete blood count panel, platelet count may be a cost-effective and noninvasive marker for CRC prognosis and a potential intervention target to prevent metastatic recurrence.
PMCID: PMC3748145  PMID: 23549858
Platelet; Thrombocytosis; CRC; Survival; Recurrence; Metastasis
5.  Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis 
Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.
We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010.
The most significant finding was related to rs879882, a variant in the 5′ region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant-containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR]=2.10, 95 % confidence interval [CI] 1.17–3.76, P=0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR=1.97, 95 % CI 0.89–4.34, P=0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR=2.63, 95 % CI 1.14–6.06 P=0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P=0.04) but not in those without chemotherapy (P=0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy.
We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients.
PMCID: PMC3721524  PMID: 22528324
Stem cell; Polymorphism; Colorectal cancer
6.  Post-diagnosis hemoglobin change associates with overall survival of multiple malignancies – results from a 14-year hospital-based cohort of lung, breast, colorectal, and liver cancers 
BMC Cancer  2013;13:340.
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
We identified 6675 patients with a diagnosis of primary lung, breast, colorectal, or liver cancer who visited the Kimmel Cancer Center at the Thomas Jefferson University from 1998 to 2011. All patients had at least two Hb measurements within the first six months after diagnosis. We analyzed the main, dose-dependent, and time-dependent effects of Hb changes on patient survival.
Compared to patients with a low Hb change (|∆Hb|≤2.6), those having a |∆Hb|>2.6 exhibited a significantly shorter survival (hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5 × 10-22, Plog rank=1.6 × 10-39). This association remained significant across the four cancer types. Bootstrap resampling validated these findings 100% of the time with P<0.01 in all patients and in patients of individual cancers. The association exhibited an apparent U-shape dose-dependent pattern. Time-dependent modeling demonstrated that the effect of Hb change on the survival of the overall patient population persisted for approximately 4.5 years after diagnosis.
Post-diagnosis Hb change associates with the survival of multiple cancers and may have clinical values in tailoring anti-anemia treatments. Because Hb level is frequently measured during cancer treatment, Hb changes may be a potentially important variable in building cancer prognosis models.
PMCID: PMC3710492  PMID: 23841898
Hemoglobin; Survival; Prognosis
7.  Relative telomere length: a novel non-invasive biomarker for the risk of non-cirrhotic hepatocellular carcinoma in patients with chronic hepatitis B infection 
European Journal of Cancer  2012;48(7):1014-1022.
Background and Aims
Telomere length has emerged as a promising risk predictor of various cancers including hepatocellular carcinoma (HCC). However, the majority of studies in this area measured telomere length in hepatocytes and one in lymphocytes with conflicting results. Moreover, no studies have been reported on using circulating DNA telomere length as a non-invasive HCC biomarker.
We conducted a nested case-control study to determine the relative telomere length (RTL) in serum DNA from 140 HBV-related HCC cases and 280 frequency-matched cancer-free HBV controls.
Cases had a significantly longer RTL (median, 0.31; range, 0.02–2.31) than controls (median, 0.20; range, 0.01–1.60) (P=0.003). Consistently, longer RTLs conferred a significantly increased HCC risk compared to short RTLs in a univariate logistic regression analysis (odds ratio [OR]=1.55, 95% confidence interval [CI]=1.02–2.33, P=0.038). This association attenuated after multivariate adjustment (OR=1.40, 95% CI=0.90–2.19, P=0.132). In a quartile analysis, a significant dose-response relationship was noted in univariate analysis (Ptrend=0.017) which was again attenuated in multivariate analysis (Ptrend=0.079). Further analyses revealed that the significant association between serum RTL and HCC risk was evident in non-cirrhotic (OR=3.54, 95% CI 1.58–7.93 P=0.002), but not cirrhotic (OR=0.95, 95% CI 0.55–1.64, P=0.860) HBV patients. Moreover, the significantly increased HCC risk conferred by cirrhosis was modulated by RTL with a significant interaction effect (Pinteraction=0.013).
RTL in circulating cell-free serum DNA could potentially be used as a novel non-invasive biomarker for non-cirrhotic HCC. Prospective cohort studies are warranted to validate this finding and assess its clinical significance in HCC prevention.
PMCID: PMC3324593  PMID: 22444598
telomere length; cirrhosis; HBV; HCC; serum
8.  Comprehensive pathway-based interrogation of genetic variations in the nucleotide excision DNA repair pathway and risk of bladder cancer 
Cancer  2011;118(1):205-215.
Growing evidence suggests that single nucleotide polymorphisms (SNPs) in nucleotide excision repair (NER) pathway genes play an important role in bladder cancer etiology. However, only a limited number of genes and variations in this pathway have been evaluated to date.
In this study, we applied a comprehensive pathway-based approach to assess the effects of 207 tagging and potentially functional SNPs in 26 NER genes on bladder cancer risk using a large case-control study consisting of 803 bladder cancer cases and 803 controls.
A total of 17 SNPs were significantly associated with altered bladder cancer risk at P<0.05, of which 7 SNPs retained noteworthiness after assessed by a Bayesian approach for the probability of false discovery. The most noteworthy SNP was rs11132186 in ING2 gene. Compared to the major allele-containing genotypes, the odds ratio (OR) was 0.52 (95% confidence interval [CI] 0.32–0.83, P = 0.005) for the homozygous variant genotype. Three additional ING2 variants also exhibited significant associations with bladder cancer risk. Significant gene-smoking interactions were observed for three of the top 17 SNPs. Furthermore, through an exploratory classification and regression tree (CART) analysis, we identified potential gene-gene interactions.
We conducted a large association study of NER pathway with bladder cancer risk and identified several novel predisposition variants. We identified potential gene-gene and gene-environment interactions in modulating bladder cancer risk. Our results reinforce the importance of a comprehensive pathway-focused and tagging SNP-based candidate gene approach to identify low-penetrance cancer susceptibility loci.
PMCID: PMC3178723  PMID: 21692063
bladder cancer; genetic susceptibility; nucleotide excision repair; SNP; gene-smoking interaction
9.  Genetic polymorphisms in pre-microRNA genes as prognostic markers of colorectal cancer 
Cumulative data has shown that microRNAs (miRNAs) are involved in the etiology and prognosis of colorectal cancer (CRC). Genetic polymorphisms in pre-miRNA genes may influence the biogenesis and functions of their host miRNAs. However, whether these polymorphisms are associated with CRC prognosis remains unknown.
We analyzed the effects of seven single nucleotide polymorphisms (SNPs) in pre-miRNA genes on the prognosis of a Chinese population with 408 CRC patients with surgically-resected adenocarcinoma.
Two SNPs were identified to be significantly associated with recurrence-free survival and overall survival of the patients. The most significant SNP was rs6505162 in pre-miR-423. Compared to the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with both the overall survival (HR=2.12, 95% CI1.34–3.34, P=0.001) and the recurrence-free survival (HR=1.59, 95% CI1.08–2.36, P=0.019). Another SNP, rs4919510 in pre-miR-608, was also associated with altered recurrence-free survival (HR=0.61, 95% CI 0.41–0.92, P=0.017). These effects were evident only in patients receiving chemotherapy but not in those without chemotherapy. In addition, the combined analysis of the two SNPs conferred a 2.84-fold (95% CI 1.50–5.37, P=0.001) increased risk of recurrence and/or death. Similarly, this effect was only prominent in those receiving chemotherapy (P<0.001) but not in those without chemotherapy (P=0.999).
Our data suggest that genetic polymorphisms in pre-miRNA genes may impact CRC prognosis especially in patients receiving chemotherapy, a finding that warrants further independent validation.
This is one of the first studies showing a prognostic role of pre-miRNA gene SNPs in CRC.
PMCID: PMC3253954  PMID: 22028396
Polymorphism; microRNA; colorectal cancer
10.  Comprehensive Analysis of Common Serum Liver Enzymes as Prospective Predictors of Hepatocellular Carcinoma in HBV Patients 
PLoS ONE  2012;7(10):e47687.
Serum liver enzymes are frequently tested in clinics to aid disease diagnosis. Large observational studies indicated that these enzymes might predict cancer risk and mortality. However, no prospective study has reported on their relationships with the risk of HBV-related hepatocellular carcinoma (HCC).
Methodology/Principal Findings
We evaluated the predictive values of four routinely tested liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) in HCC risk in a prospectively enrolled clinical cohort of 588 Korean American HBV patients. For all four enzymes, the baseline level as well as the average and maximum levels during the first 1 or 2 years of follow-up were analyzed using multivariate Cox proportional hazards model. Patients were categorized into a normal or an elevated group based on the clinical cut-off of each enzyme. During a median follow-up of 7.5 years, 52 patients (incidence rate, 8.8%) developed HCC. The incidence rates were higher in the elevated groups for all four enzymes. The most significant finding was for GGT, with the highest incidence rate of 16.4% in the elevated group compared to 4.6% in the normal group (P<0.001). Compared to patients with normal baseline GGT, those with elevated GGT exhibited a significantly increased HCC risk with a hazards ratio (HR) of 2.60 (95% confidence interval [CI], 1.41–4.77, P = 0.002). Further analyses revealed a cumulative effect between baseline GGT and ALP (HR = 3.41, 95% CI 1.54–7.56, P = 0.003).
Conclusions Significance
Serum GGT might predict HCC risk in HBV patients individually or jointly with other enzymes.
PMCID: PMC3480412  PMID: 23112834
11.  Prognostic Significance of Ataxia-Telangiectasia Mutated, DNA-dependent Protein Kinase Catalytic Subunit, and Ku Heterodimeric Regulatory Complex 86-kD Subunit Expression in Patients With Nonsmall Cell Lung Cancer 
Cancer  2008;112(12):2756-2764.
The double-strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and the Ku heterodimeric regulatory complex 86-kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.
mRNA expression levels of ATM, DNA-PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real-time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan-Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.
mRNA expression of ATM and DNA-PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA-PKcs were associated significantly with a 1.82-fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13-fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan-Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA-PKcs had notably shorter median survival than patients with low ratios.
The current findings suggested that the T/N expression ratios of ATM and DNA-PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy.
PMCID: PMC3384998  PMID: 18457328
DNA repair; DNA double-strand break; nonsmall cell lung cancer; prognosis
12.  Genetic Polymorphism in a VEGF-Independent Angiogenesis Gene ANGPT1 and Overall Survival of Colorectal Cancer Patients after Surgical Resection 
PLoS ONE  2012;7(4):e34758.
The VEGF-independent angiogenic signaling plays an important role in the development of colorectal cancer (CRC). However, its implication in the clinical outcome of CRC has not been reported. This study aimed to investigate the association between genetic variations in several major VEGF-independent signaling pathway genes and the overall survival of CRC patients.
Seven single nucleotide polymorphisms (SNPs) in four important VEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4 and ENG) were genotyped in a Chinese population with 408 CRC patients.
One SNP, rs1954727 in ANGPT1, was significantly associated with CRC overall survival. Compared to patients with the homozygous wild-type genotype of rs1954727, those with heterozygous and homozygous variant genotypes exhibited a favorable overall survival with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.55–1.43, P = 0.623), and 0.32 (95% CI 0.15–0.71, P = 0.005), respectively (P trend = 0.008). In stratified analysis, this association remained significant in patients receiving chemotherapy (P trend = 0.012), but not in those without chemotherapy. We further evaluated the effects of chemotherapy on CRC survival that was stratified by rs1954727 genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRC patients (HR = 0.44, 95% CI 0.26–0.75, P = 0.002), which was especially prominent in those patients with the heterozygous genotype of rs1954727 (HR = 0.45, 95%CI 0.22–0.92, P = 0.028).
Our data suggest that rs1954727 in ANGPT1 gene might be a prognostic biomarker for the overall survival of CRC patients, especially in those receiving chemotherapy, a finding that warrants validation in larger independent populations.
PMCID: PMC3319640  PMID: 22496856
13.  A Meta-Analysis of Array-CGH Studies Implicates Antiviral Immunity Pathways in the Development of Hepatocellular Carcinoma 
PLoS ONE  2011;6(12):e28404.
The development and progression of hepatocellular carcinoma (HCC) is significantly correlated to the accumulation of genomic alterations. Array-based comparative genomic hybridization (array CGH) has been applied to a wide range of tumors including HCCs for the genome-wide high resolution screening of DNA copy number changes. However, the relevant chromosomal variations that play a central role in the development of HCC still are not fully elucidated.
In present study, in order to further characterize the copy number alterations (CNAs) important to HCC development, we conducted a meta-analysis of four published independent array-CGH datasets including total 159 samples.
Eighty five significant gains (frequency ≥25%) were mostly mapped to five broad chromosomal regions including 1q, 6p, 8q, 17q and 20p, as well as two narrow regions 5p15.33 and 9q34.2-34.3. Eighty eight significant losses (frequency ≥25%) were most frequently present in 4q, 6q, 8p, 9p, 13q, 14q, 16q, and 17p. Significant correlations existed between chromosomal aberrations either located on the same chromosome or the different chromosomes. HCCs with different etiologies largely exhibited surprisingly similar profiles of chromosomal aberrations with only a few exceptions. Furthermore, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the genes affected by these chromosomal aberrations were significantly enriched in 31 canonical pathways with the highest enrichment observed for antiviral immunity pathways.
Taken together, our findings provide novel and important clues for the implications of antiviral immunity-related gene pathways in the pathogenesis and progression of HCC.
PMCID: PMC3236189  PMID: 22174799
14.  RNA-Seq Analyses Generate Comprehensive Transcriptomic Landscape and Reveal Complex Transcript Patterns in Hepatocellular Carcinoma 
PLoS ONE  2011;6(10):e26168.
RNA-seq is a powerful tool for comprehensive characterization of whole transcriptome at both gene and exon levels and with a unique ability of identifying novel splicing variants. To date, RNA-seq analysis of HBV-related hepatocellular carcinoma (HCC) has not been reported. In this study, we performed transcriptome analyses for 10 matched pairs of cancer and non-cancerous tissues from HCC patients on Solexa/Illumina GAII platform. On average, about 21.6 million sequencing reads and 10.6 million aligned reads were obtained for samples sequenced on each lane, which was able to identify >50% of all the annotated genes for each sample. Furthermore, we identified 1,378 significantly differently expressed genes (DEGs) and 24, 338 differentially expressed exons (DEEs). Comprehensive function analyses indicated that cell growth-related, metabolism-related and immune-related pathways were most significantly enriched by DEGs, pointing to a complex mechanism for HCC carcinogenesis. Positional gene enrichment analysis showed that DEGs were most significantly enriched at chromosome 8q21.3–24.3. The most interesting findings were from the analysis at exon levels where we characterized three major patterns of expression changes between gene and exon levels, implying a much complex landscape of transcript-specific differential expressions in HCC. Finally, we identified a novel highly up-regulated exon-exon junction in ATAD2 gene in HCC tissues. Overall, to our best knowledge, our study represents the most comprehensive characterization of HBV-related HCC transcriptome including exon level expression changes and novel splicing variants, which illustrated the power of RNA-seq and provided important clues for understanding the molecular mechanisms of HCC pathogenesis at system-wide levels.
PMCID: PMC3197143  PMID: 22043308
15.  Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk 
Carcinogenesis  2010;31(10):1762-1769.
Background: DNA strand breaks pose the greatest threat to genomic stability. Genetically determined mutagen sensitivity predisposes individuals to a variety of cancers, including glioma. However, polymorphisms in DNA strand break repair genes that may determine mutagen sensitivity are not well studied in cancer risk, especially in gliomas.
Methods: We correlated genotype data for tag single-nucleotide polymorphisms (tSNPs) of DNA strand break repair genes with a gamma-radiation-induced mutagen sensitivity phenotype [expressed as mean breaks per cell (B/C)] in samples from 426 glioma patients. We also conducted analysis to assess joint and haplotype effects of single-nucleotide polymorphisms (SNPs) on mutagen sensitivity. We further validate our results in an independent external control group totaling 662 subjects.
Results: Of the 392 tSNPs examined, we found that mutagen sensitivity was modified by one tSNP in the EME2 gene and six tSNPs in the RAD51L1 gene (P < 0.01). Among the six RAD51L1 SNPs tested in the validation set, one (RAD51L1 rs2180611) was significantly associated with mutagen sensitivity (P = 0.025). Moreover, we found a significant dose–response relationship between the mutagen sensitivity and the number of adverse tSNP genotypes. Furthermore, haplotype analysis revealed that RAD51L1 haplotypes F-A (zero adverse allele) and F-E (six adverse alleles) exhibited the lowest (0.42) and highest (0.93) mean B/C values, respectively. A similar dose–response relationship also existed between the mutagen sensitivity and the number of adverse haplotypes.
Conclusion: These results suggest that polymorphisms in and haplotypes of the RAD51L1 gene, which is involved in the double-strand break repair pathway, modulate gamma-radiation-induced mutagen sensitivity.
PMCID: PMC2981459  PMID: 20610542
16.  MicroRNA Expression Signatures in Barrett’s Esophagus and Esophageal Adenocarcinoma 
Esophageal adenocarcinoma (EAC) is a highly aggressive malignancy that frequently develops from Barrett’s esophagus (BE), a premalignant pathological change occurring in the lower end of esophagus. To identify BE patients at high risk of malignant transformation is essential to the prevention of EAC. Although microRNA (miRNA) expression signatures have been associated with the etiology and prognosis of several types of cancers, their roles in the development of EAC have not been extensively evaluated.
Experimental Design
In this study, we analyzed the expression patterns of 470 human miRNAs using Agilent miRNA microarray in 32 disease/normal-paired tissues from 16 patients diagnosed with BE of either low or high grade dysplasia, or EAC.
Using unsupervised hierarchical clustering and class comparison analyses, we found that miRNA expression profiles in tissues of BE with high grade dysplasia were significantly different from their corresponding normal tissues. Similar findings were observed for EAC, but not for BE with low grade dysplasia. The expression patterns of selected miRNAs were further validated using quantitative reverse transcription real-time PCR in an independent set of 75 pairs of disease/normal tissues. Finally, we identified several miRNAs that were involved in the progressions from low grade dysplasia BE to EAC.
We showed that miRNAs were involved in the development and progression of EAC. The identified significant miRNAs may become potential targets for early detection, chemoprevention, and treatment of esophageal cancer.
PMCID: PMC2745487  PMID: 19737949
microRNA; Barrett’s esophagus; Esophageal adenocarcinoma
17.  Genetic susceptibility to esophageal cancer: the role of the nucleotide excision repair pathway 
Carcinogenesis  2009;30(5):785-792.
In this case–control study with 387 White esophageal patients and 462 White controls matched to cases by age and sex, we evaluated the associations between 13 potential functional polymorphisms in eight major nucleotide excision repair (NER) genes and esophageal cancer risk. In individual single nucleotide polymorphism analysis, after adjustment for multiple comparisons, the heterozygous GT genotype of the ERCC1 3′ untranslated region (UTR) was associated with an increased risk, whereas the homozygous variant genotype TT was associated with 60% reduction in risk with an odds ratio (OR) of 0.40 (95% confidence interval [CI] = 0.19–0.86). The heterozygous AG genotype of XPA 5′ UTR was at 2.11-fold increased risk (95% CI = 1.33–3.35) and the risk reached 3.10-fold (95% CI = 1.94–4.95) for the homozygous variant GG genotype. These associations were also significant when restricted the analyses in patients with esophageal adenocarcinoma. Further, the CT genotype of the RAD23B Ala249Val was associated with increased esophageal cancer risk (OR = 1.44; 95% CI = 1.05–1.97), whereas the poly-AT−/+ genotype of the XPC intron 9 conferred a decreased risk (OR = 0.71, 95% CI = 0.51–0.97). In joint analysis, individuals carrying 1 (OR = 2.64, 95% CI = 1.57–4.52) and ≥2 (OR = 2.74, 95% CI = 1.58–4.75) unfavorable genotypes exhibited significantly increased risk for esophageal cancer risk with significant dose-response trend (P for trend = 0.006). The pathway-based risk was more evident in ever smokers, overweight/obese individuals, men and ever drinkers. Our results support the hypothesis that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of esophageal cancer. These findings warrant further replications in different populations.
PMCID: PMC2675653  PMID: 19270000
18.  Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p are associated with an increased risk for esophageal cancer 
Background and Purpose
Short telomere may cause chromosomal instability in Barrett's esophagus and thus promote tumorigenesis. However, whether short telomere length in all chromosomes or just some of them is associated with increased esophageal cancer (EC) risk is largely unknown. To address this question, we examined the overall and chromosome-specific telomere lengths of 17p, 12q, 2p, and 11q and assessed their associations with EC risk.
In a case-control study with 94 EC cases and 94 matched controls, the overall telomere length and the chromosome-specific telomere lengths of 17p, 12q, 2p and 11q in peripheral blood lymphocytes were determined by a real-time polymerase chain reaction and a modified single telomere length analysis assay, respectively. Multi-variate logistic regression analysis was used to assess the association between telomere length and EC risk.
Compared with controls, EC patients had significantly shorter overall telomere lengths (P = 0.004) and chromosome-specific telomere lengths of 17p (P = 0.003) and 12q (P = 0.006) but not of 11q (P = 0.632) and 2p (P = 0.972). Furthermore, the multi-variate logistic regression analysis showed that the short overall telomere length and chromosome-specific telomere lengths of 17p and 12q were associated with a dose-dependent increase in EC risk.
Our study provides the first epidemiological evidence that short telomere length of 17p and 12q play an important role in esophageal carcinogenesis, suggesting that short telomere length of specific chromosomes is associated with the etiology of different cancer types.
PMCID: PMC2701666  PMID: 19401529
Telomere length; esophageal cancer; genetic instability
19.  Mitochondrial DNA Content: Its Genetic Heritability and Association With Renal Cell Carcinoma 
The extent to which mitochondrial DNA (mtDNA) content (also termed mtDNA copy number) in normal human cells is influenced by genetic factors has yet to be established. In addition, whether inherited variation of mtDNA content in normal cells contributes to cancer susceptibility remains unclear. Renal cell carcinoma accounts for 85% of all renal cancers. No studies have investigated the association between mtDNA content and the risk of renal cell carcinoma.
We first used a classic twin study design to estimate the genetic contribution to the determination of mtDNA content. mtDNA content was measured by quantitative real-time polymerase chain reaction in peripheral blood lymphocytes from 250 monozygotic twins, 92 dizygotic twins, and 33 siblings (ie, individual siblings of a pair of twins). We used biometric genetic modeling to estimate heritability of mtDNA content. We then used a case–control study with 260 case patients with renal cell carcinoma and 281 matched control subjects and multivariable logistic regression analysis to examine the association between mtDNA content in peripheral blood lymphocytes and the risk of renal cell carcinoma. All statistical tests were two-sided.
The heritability (ie, proportion of phenotypic variation in a population that is attributable to genetic variation among individuals) of mtDNA content was 65% (95% confidence interval [CI] = 50% to 72%; P < .001). Case patients with renal cell carcinoma had a statistically significantly lower mtDNA content (1.18 copies) than control subjects (1.29 copies) (difference = 0.11, 95% CI = 0.03 to 0.17; P = .006). Low mtDNA content (ie, less than the median in control subjects) was associated with a statistically significantly increased risk of renal cell carcinoma, compared with high content (odds ratio = 1.53, 95% CI = 1.07 to 2.19). In a trend analysis, a statistically significant dose–response relationship was detected between lower mtDNA content and increasing risk of renal cell carcinoma (P for trend <.001).
mtDNA content appears to have high heritability. Low mtDNA content appears to be associated with increased risk of renal cell carcinoma.
PMCID: PMC2720693  PMID: 18664653

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