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author:("Yang, huashan")
1.  Global assessment of genetic variation influencing response to retinoid chemoprevention in head and neck cancer patients 
Head and neck squamous cell carcinoma (HNSCC) patients are at an increased risk of developing a second primary tumor (SPT) or recurrence following curative treatment. 13-cis-retinoic acid (13-cRA) has been tested in chemoprevention clinical trials but the results have been inconclusive. We genotyped 9,465 SNPs in 450 patients from the Retinoid Head and Neck Second Primary Trial. SNPs were analyzed for associations with SPT/recurrence in patients receiving placebo to identify prognosis markers and further analyzed for effects of 13-cRA in patients with these prognostic loci. Thirteen loci identified a majority subgroup of patients at a high risk of SPT/recurrence and in whom 13-cRA was protective. Patients carrying the common genotype of rs3118570 in the retinoid X receptor (RXRA) were at a 3.33-fold increased risk (95% confidence interval [CI], 1.67–6.67) and represented over 70% of the study population. This locus also identified individuals who received benefit from chemoprevention with a 38% reduced risk (95% CI, 0.43–0.90). Analyses of cumulative effect and potential gene-gene interactions also implicated CDC25C:rs6596428 and JAK2:rs1887427 as two other genetic loci with major roles in prognosis and 13-cRA response. Patients with all three common genotypes had a 76% reduction in SPT/recurrence (95% CI, 0.093–0.64) following 13-cRA chemoprevention. Carriers of these common genotypes constituted a substantial percentage of the study population, indicating that a pharmacogenetics approach could help select patients for 13-cRA chemoprevention. The lack of any alternatives for reducing risk in these patients highlights the need for future clinical trials to prospectively validate our findings.
doi:10.1158/1940-6207.CAPR-10-0125
PMCID: PMC3955084  PMID: 21292633
HNSCC; SPT; single nucleotide polymorphisms; retinoids
2.  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 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.ejca.2012.02.065
PMCID: PMC3382017  PMID: 22436980
Alpha-fetoprotein (AFP); hepatitis B virus (HBV); hepatocellular carcinoma (HCC)
3.  Preoperative Platelet Count Associates with Survival and Distant Metastasis in Surgically Resected Colorectal Cancer Patients 
Objective
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.
Design
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.
Results
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.
Conclusion
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.
doi:10.1007/s12029-013-9491-9
PMCID: PMC3748145  PMID: 23549858
Platelet; Thrombocytosis; CRC; Survival; Recurrence; Metastasis
4.  Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s12029-012-9388-z
PMCID: PMC3721524  PMID: 22528324
Stem cell; Polymorphism; Colorectal cancer
5.  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.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1471-2407-13-340
PMCID: PMC3710492  PMID: 23841898
Hemoglobin; Survival; Prognosis
6.  Prostate cancer biomarker: a key field to explore 
Asian Journal of Andrology  2013;15(3):358-359.
doi:10.1038/aja.2013.1
PMCID: PMC3739636  PMID: 23435472
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ejca.2012.02.066
PMCID: PMC3324593  PMID: 22444598
telomere length; cirrhosis; HBV; HCC; serum
8.  Profiling HBV integrations in hepatocellular carcinoma 
doi:10.3978/j.issn.2304-3881.2012.10.13
PMCID: PMC3924654  PMID: 24570928
9.  Genetic polymorphisms in pre-microRNA genes as prognostic markers of colorectal cancer 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Impact
This is one of the first studies showing a prognostic role of pre-miRNA gene SNPs in CRC.
doi:10.1158/1055-9965.EPI-11-0624
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.
Background
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.
doi:10.1371/journal.pone.0047687
PMCID: PMC3480412  PMID: 23112834
11.  ATM sequence variants associate with susceptibility to non-small cell lung cancer 
ATM gene mutations have been implicated in many human cancers. However, the role of ATM polymorphisms in lung carcinogenesis is largely unexplored. We conducted a case-control analysis of 556 Caucasian non-small-cell lung cancer (NSCLC) patients and 556 controls frequency-matched on age, gender and smoking status. We genotyped 11 single nucleotide polymorphisms of the ATM gene and found that compared with the wild-type allele-containing genotypes, the homozygous variant genotypes of ATM08 (rs227060) and ATM10 (rs170548) were associated with elevated NSCLC risk with ORs of 1.55 (95% CI: 1.02–2.35) and 1.51 (0.99–2.31), respectively. ATM haplotypes and diplotypes were inferred using the Expectation-Maximization algorithm. Haplotype H5 was significantly associated with reduced NSCLC risk in former smokers with an OR of 0.47 (0.25–0.96) compared with the common H1 haplotype. Compared with the H1–H2 diplotype, H2–H2 and H3–H4 diplotypes were associated with increased NSCLC risk with ORs of 1.58 (0.99–2.54) and 2.29 (1.05–5.00), respectively. We then evaluated genotype–phenotype correlation in the control group using the comet assay to determine DNA damage and DNA repair capacity. Compared with individuals with at least 1 wild-type allele, the homozygous variant carriers of either ATM08 or ATM10 exhibited significantly increased DNA damage as evidenced by a higher mean value of the radiation-induced olive tail moment (ATM08: 4.86 ± 2.43 vs. 3.79 ± 1.51, p = 0.04; ATM10: 5.14 ± 2.37 vs. 3.79 ± 1.54, p = 0.01). Our study presents the first epidemiologic evidence that ATM genetic variants may affect NSCLC predisposition, and that the risk-conferring variants might act through down-regulating the functions of ATM in DNA repair activity upon genetic insults such as ionizing radiation.
doi:10.1002/ijc.22918
PMCID: PMC3477817  PMID: 17582598
ATM; polymorphism; haplotype; diplotype; NSCLC
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.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1371/journal.pone.0034758
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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0028404
PMCID: PMC3236189  PMID: 22174799
14.  MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer 
Carcinogenesis  2010;31(12):2118-2123.
Second primary tumor (SPT) and/or recurrence negatively impact the prognosis of patients with curatively treated early-stage head and neck cancer. MicroRNAs (miRNAs) play important roles in cancer development. We explored whether the variations of miRNA-related pathway were associated with the risk of SPT/recurrence in patients with early-stage head and neck cancer. This study includes 150 early-stage head and neck cancer patients with SPT/recurrence and 300 patients without SPT/recurrence. Two hundred and thirty-five tagging and potentially functional single-nucleotide polymorphisms (SNPs) were genotyped from eight miRNA biogenesis pathway genes and 135 miRNA-targeted genes. Eighteen miRNA-related SNPs were significantly associated with the risk of SPT/recurrence. The most significant SNP was rs3747238, a miRNA-binding site SNP in SMC1B. The variant homozygous genotype of this SNP was associated with a 1.74-fold increased risk [95% confidence interval (CI) 1.19–2.54; P = 0.004]. Cumulative effect analysis showed joint effects for the number of unfavorable genotype in patients. Survival tree analysis further identified the high-order gene–gene interactions and categorized the study subjects into low-, medium- and high-risk groups. Patients in the high-risk group had a 4.84-fold increased risk (95% CI: 3.11–7.51; P = 2.45 × 10−12) and a shorter event-free median survival time of 37.9 months (log rank P = 2.28 × 10−13). Our results suggested that miRNA-related genetic polymorphisms may be used individually and jointly to predict the risk of SPT/recurrence of early-stage head and neck cancer patients.
doi:10.1093/carcin/bgq177
PMCID: PMC3105587  PMID: 20819778
15.  Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma 
Carcinogenesis  2010;31(10):1755-1761.
Curatively treated patients with early-stage head and neck squamous cell carcinoma (HNSCC) are at high risks for second primary tumor (SPT) and recurrence. The regulator of G-protein signaling (RGS) is important in essential signaling transduction and cellular activities. We hypothesize that genetic variations of RGS may modulate the risk of SPT/recurrence in patients with early-stage HNSCC. In a nested case–control study, we evaluated 98 single-nucleotide polymorphisms (SNPs) in 17 RGS genes for the risk of SPT/recurrence among 450 HNSCC patients. Eight SNPs showed significant associations with the risk of SPT/recurrence, with the most significant one of rs2179653, which is located in the 5′-flanking region of RGS2 gene. Under a recessive genetic model, the homozygous variant genotype of this SNP was associated with 2.95-fold [95% confidence interval (CI): 1.52–5.74] increased risk of SPT/recurrence. This association remained significant after the adjustment for multiple comparisons. Cumulative effects analysis revealed that the risk increased significantly with the increasing numbers of unfavorable genotypes. Compared with subjects carrying 0–2 unfavorable genotypes, the hazard ratios (95% CIs) for those carrying 3 or 4+ were 1.73 (1.10–2.70) and 3.05 (1.92–4.83), respectively. Furthermore, survival tree analysis revealed potential higher order gene–gene interactions and indicated different outcomes based on distinct genotype profiles. Genetic variations of RGS genes may modulate the susceptibility to SPT/recurrence in early-stage HNSCC patients individually and cumulatively. Our results stressed the importance of taking a polygenic approach to evaluate the cumulative and interaction effects of genetic variations in the prediction of cancer risk and prognosis.
doi:10.1093/carcin/bgq138
PMCID: PMC2950933  PMID: 20627871
16.  Genetic Variations in the Sonic Hedgehog Pathway Affect Clinical Outcomes in Non-muscle–invasive Bladder Cancer 
Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes; therefore, we genotyped 177 SNPs in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non-muscle invasive bladder cancer (NMIBC) and 318 cases of muscle invasive and metastatic bladder cancer (MiMBC). Only 3 SNPs (GLI3 rs3823720, rs3735361, rs10951671) reached nominal significance in association with risk (P≤0.05), which became non-significant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P≤0.05), of which 2 (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients with P-values of 1.0×10−3 (SHH rs1233560) and 1.3×10−3 (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guérin (BCG; P≤0.05), of which 2, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P=2×10−4 and 9×10−4, respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although 3 SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P≤0.05), none remained significant after multiple-comparison adjustments. Germline genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients.
doi:10.1158/1940-6207.CAPR-10-0035
PMCID: PMC2955764  PMID: 20858759
sonic hedgehog pathway; cancer risk; recurrence; BCG; non-muscle invasive bladder cancer
17.  Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk 
Carcinogenesis  2009;30(12):2047-2052.
Genetic variations in phosphoinositide-3 kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single-nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, four SNPs in regulatory associated protein of mTOR (RAPTOR) remained significant after correcting for multiple testing: rs11653499 [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.24–2.60, P = 0.002], rs7211818 (OR: 2.13, 95% CI: 1.35–3.36, P = 0.001), rs7212142 (OR: 1.57, 95% CI: 1.19–2.07, P = 0.002) and rs9674559 (OR: 2.05, 95% CI: 1.31–3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared with the most common haplotypes, haplotype containing the rs7212142 wild-type allele showed a protective effect of bladder cancer (OR: 0.83, 95% CI: 0.70–0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95% CI: 1.09–1.60). In combined analysis of three independent significant RAPTOR SNPs (rs11653499, rs7211818 and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend <0.001). Compared with the subjects without any of the unfavorable genotypes, those carrying all three unfavorable genotypes showed a 2.22-fold (95% CI: 1.33–3.71) increased bladder cancer risk. This is the first study to evaluate the role of germ line genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors that will help us identify high-risk individuals for bladder cancer.
doi:10.1093/carcin/bgp258
PMCID: PMC2792319  PMID: 19875696
18.  Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays 
Purpose
The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis, and treatment.
Methods
We applied Illumina's 317K high-density SNP-arrays to profile chromosomal aberrations in clear cell renal cell carcinoma (ccRCC) from 80 patients and analyzed the association of LOH/amplification events with clinicopathological characteristics and telomere length.
Results
The most common loss of heterozygosity (LOH) were 3p (69 cases) including 38 whole 3p arm losses, 30 large fragment LOH (spanning 3p21-36), and 1 interstitial LOH (spanning 3p12-14, 3p21-22, 3p24.1-24.2, and 3p24.3), followed by chromosome losses at 8p12-pter, 6q23.3-27, 14q24.1-qter, 9q32-qter, 10q22.3-qter, 9p13.3-pter, 4q28.3-qter, and 13q12.1-21.1. We also found several smallest overlapping regions of LOH that contained tumor suppressor genes. One smallest LOH in 8p12 had a size of 0.29 Mb and only contained one gene (NRG1). The most frequent chromosome gains were at 5q (32 cases), including 10 whole 5q amplification, 21 large amplifications encompassing 5q32-ter, and 1 focal amplification in 5q35.3 (0.42 Mb). The other common chromosome gains were 1q25.1-qter, 7q21.13-qter, 8q24.12-qter, and whole 7p arm. Significant associations of LOH at 9p, 9q, 14q, and 18q were observed with higher nuclear grade. Significant associations with tumor stage were observed for LOH at 14q, 18p, and 21q. Finally, we found that tumors with LOH at 2q, 6p, 6q, 9p, 9q, and 17p had significantly shorter telomere length than those without LOH.
Conclusion
This is the first study to use Illumina's SNP-CGH array that provides a close estimate of the size and frequency of chromosome LOH and amplifications of ccRCC. The identified regions and genes may become diagnostic and prognostic biomarkers as well as potential targets of therapy.
doi:10.1002/ijc.24642
PMCID: PMC2768265  PMID: 19521957
19.  Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large Scale Evaluation of Genetic Variants 
Background
This study was aimed to identify novel susceptibility variants for second primary tumor (SPT) or recurrence in curatively treated early stage head and neck squamous cell carcinoma (HNSCC) patients.
Methods
We constructed a custom chip containing a comprehensive panel of 9645 chromosomal and mitochondrial single nucleotide polymorphisms (SNPs) representing 998 cancer-related genes selected by a systematic prioritization schema. Using this chip, we genotyped 150 early-stage HNSCC patients with and 300 matched patients without SPT/recurrence from a prospectively conducted randomized trial and assessed the association of these SNPs with risk of SPT/recurrence.
Results
Individually, six chromosomal SNPs and seven mitochondrial SNPs (mtSNPs) were significantly associated with risk of SPT/recurrence after adjustment for multiple comparisons. A strong gene-dosage effect was observed these SNPs were combined, as evidenced by a progressively increasing SPT/recurrence risk as the number of unfavorable genotypes increased (P for trend < 1.00×10−20). Several polygenic analyses suggest an important role of interconnected functional network and gene-gene interaction in modulating SPT/recurrence. Furthermore, incorporation of these genetic markers into a multivariate model improved significantly the discriminatory ability over the models containing only clinical and epidemiologic variables.
Conclusions
This is the first large scale systematic evaluation of germline genetic variants for their roles in HNSCC SPT/recurrence. The study identified several promising susceptibility loci and demonstrated the cumulative effect of multiple risk loci in HNSCC SPT/recurrence. Furthermore, this study underscores the importance of incorporating germline genetic variation data with clinical and risk factor data in constructing prediction models for clinical outcomes.
doi:10.1158/1940-6207.CAPR-09-0025
PMCID: PMC2964280  PMID: 19584075
iSelect Infinium; Single nucleotide polymorphisms; Head and neck cancer; Secondary primary tumor; recurrence
20.  MicroRNA Expression Signatures in Barrett’s Esophagus and Esophageal Adenocarcinoma 
Purpose
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.
Results
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.
Conclusions
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.
doi:10.1158/1078-0432.CCR-09-0385
PMCID: PMC2745487  PMID: 19737949
microRNA; Barrett’s esophagus; Esophageal adenocarcinoma
21.  Cyclooxygenase-2 Gene Polymorphisms Reduce Risk of Oral Premalignant Lesions 
Cancer  2009;115(7):1498-1506.
Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. The overexpression of cyclooxygenase-2 (COX-2) gene is frequently found in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single nucleotide polymorphisms (SNPs) of COX-2 gene have been associated with the risk of multiple cancers, but their effects on OPL susceptibility have not been sufficiently evaluated. Here we conducted a case-control study including 147 patients with OPL and 147 healthy matched controls. We evaluated the effects of three potentially functional COX-2 polymorphisms, including −765G>C (rs20417), exon10+837T>C (rs5275), and exon10−90C>T (rs689470), on OPL risk. We found that the variant-containing genotypes of COX-2 exon10+837T>C variant were associated with a significantly reduced OPL risk with an odds ratio (OR) of 0.48 (95% CI, 0.28−0.80). This protective effect was also significant in males, younger subjects, ever smokers, and ever drinkers. Consistently, a common haplotype (WMW, in the order of −765G>C, exon10+837T>C, and exon10−90C>T; W, wild-type allele, M, variant allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon10+837T>C were both associated with a reduced OPL risk, having ORs of 0.55 (95% CI, 0.33−0.93) and 0.44 (95% CI, 0.22−0.89), respectively. In addition, using never smokers with the variant-containing genotypes as the reference group, we observed an interaction effects between specific COX-2 variants and tobacco smoking in the modulation of OPL risk. Overall, our results provided the first epidemiological evidence indicating that potentially functional polymorphisms of the COX-2 gene may impact OPL susceptibility.
doi:10.1002/cncr.24157
PMCID: PMC2666299  PMID: 19197984
COX-2; polymorphism; haplotype; diplotype; oral premalignant lesion
22.  Genetic Variations in the PI3K/PTEN/AKT/mTOR Pathway Are Associated With Clinical Outcomes in Esophageal Cancer Patients Treated With Chemoradiotherapy 
Journal of Clinical Oncology  2009;27(6):857-871.
Purpose
The phosphoinositide-3-kinase (PI3K), phosphatase and tensin homolog (PTEN), v-akt murine thymoma viral oncogene homolog (AKT), and mammalian target of rapamycin (mTOR) signaling pathway has been implicated in resistance to several chemotherapeutic agents. In this retrospective study, we determined whether common genetic variations in this pathway are associated with clinical outcomes in esophageal cancer patients with adenocarcinoma or squamous cell carcinoma who have undergone chemoradiotherapy and surgery.
Patients and Methods
Sixteen tagging single nucleotide polymorphisms (SNPs) in PIK3CA, PTEN, AKT1, AKT2, and FRAP1 (encoding mTOR) were genotyped in these patients and analyzed for associations with response to therapy, survival, and recurrence.
Results
We observed an increased recurrence risk with genetic variations in AKT1 and AKT2 (hazard ratio [HR], 2.21; 95% CI, 1.06 to 4.60; and HR, 3.30; 95% CI, 1.64 to 6.66, respectively). This effect was magnified with an increasing number of AKT adverse genotypes. In contrast, a predictable protective effect by PTEN genetic variants on recurrence was evident. Survival tree analysis identified higher-order interactions that resulted in variation in recurrence-free survival from 12 to 42 months, depending on the combination of SNPs. Genetic variations in AKT1, AKT2, and FRAP1 were associated with survival. Patients homozygous for either of the FRAP1 SNPs assayed had a more than three-fold increased risk of death. Two genes—AKT2 and FRAP1—were associated with a poor treatment response, while a better response was associated with heterozygosity for AKT1:rs3803304 (odds ratio, 0.50; 95% CI, 0.25 to 0.99).
Conclusion
These results suggest that common genetic variations in this pathway modulate clinical outcomes in patients who undergo chemoradiotherapy. With further validation, these results may be used to build a model of individualized therapy for the selection of the optimal chemotherapeutic regimen.
doi:10.1200/JCO.2008.17.6297
PMCID: PMC2738430  PMID: 19164214
23.  BPDE-Induced Lymphocytic Chromosome 3p Deletions May Predict Renal Cell Carcinoma Risk 
The Journal of urology  2008;179(6):2416-2421.
Purpose
Cigarette smoking is a risk factor for renal cell carcinoma (RCC). Benzo[α]pyrene diol expoxide (BPDE), a major constituent of cigarette smoke, induces 3p aberrations that are associated with susceptibility to other smoking-associated cancers. Because chromosome 3p deletions are known to the most frequent genetic alterations in RCC, we tested whether 3p sensitivity to BPDE predicted susceptibility to RCC.
Material and Methods
Cultured peripheral blood lymphocytic cells from 170 cases and 135 control subjects were treated with 2 μM BPDE for 24 hours and assessed for 3p deletions by flourescenence in situ hybridization using probes directed to 3p25.2, 3p21.3, 3p14.2, and 3p12.2; a probe for 3q13 was used as a control. One thousand lymphocyte interphases were scored for each sample.
Results
At each locus, BPDE-induced 3p deletions were significantly more frequent in cases than in controls. No significant differences between cases and controls were observed for deletions in 3q13. Using the median value in the controls as the cutoff point for BPDE sensitivity, we found the odds ratios for subjects with high BPDE sensitivity at 3p25.2, 3p21.3, 3p14.2, and 3p12.2 were 2.02 (95% confidence interval [CI], 1.15–3.37), 2.28 (95% CI, 1.07–3.16), 1.84 (95% CI, 1.33–3.92), and 1.97 (95% CI, 1.18–3.46), respectively. There were dose-dependent relationships between the number of deletions at each locus and risk for RCC.
Conclusions
This study demonstrated that chromosome 3p may be a specific molecular target of cigarette carcinogens and that BPDE sensitivity in chromosome 3p may reflect an individual’s genetic susceptibility to RCC.
doi:10.1016/j.juro.2008.01.092
PMCID: PMC2810745  PMID: 18433782
Renal cell carcinoma; BPDE; chromosome 3p; smoking; lymphocyte
24.  Single nucleotide polymorphisms of microRNA-machinery genes modify the risk of renal cell carcinoma 
Purpose
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that have been implicated in a wide diversity of basic cellular functions through post-transcriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA-machinery genes could be associated with the risk of renal cell carcinoma (RCC).
Experimental Design
We genotyped 40 single nucleotide polymorphisms (SNPs) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, EIF2C1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with RCC and 278 matched controls.
Results
We found that two SNPs in the GEMIN4 gene were significantly associated with altered RCC risks. The variant containing genotypes of the Asn929Asp and Cys1033Arg exhibited a significantly reduced risk with an odds ratio [OR] of 0.67 (95% confidence interval [CI], 0.47–0.96) and 0.68 (95% CI, 0.47–0.98), respectively. Haplotype analysis showed that a common haplotype of the GEMIN4 was associated with a significant reduce in risk of RCC (OR, 0.66; 95% CI, 0.45–0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group within one unfavorable genotype, the median-risk and high-risk group exhibited a 1.55-fold (95% CI, 0.96–2.50) and a 2.49-fold (95% CI, 1.58–3.91) increased risk of RCC, respectively (P for trend <0.001).
Conclusion
Our results suggested that genetic polymorphisms of the miRNA-machinery genes may impact RCC susceptibility individually and jointly.
doi:10.1158/1078-0432.CCR-08-1199
PMCID: PMC2650498  PMID: 19047128
renal cell carcinoma; microRNA-machinery gene; single nucleotide polymorphism; cancer susceptibility; molecular epidemiology
25.  Genetic Variations in microRNA-related Genes Are Novel Susceptibility Loci for Esophageal Cancer Risk 
MicroRNAs (miRNAs) can act as oncogenes or tumor suppressors and modulate the expression of approximately one-third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single-nucleotide polymorphisms (SNPs) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal-cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequencymatched (age, gender, and ethnicity) controls. Seven SNPs were significantly associated with esophageal cancer risk. The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 (95% confidence interval [CI], 0.51-0.80; P for trend < 0.0001). This association remained significant after we corrected for multiple comparisons. A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio = 0.65; 95% CI, 0.42-0.99). We performed a combined unfavorable genotype analysis to further evaluate the cumulative effects of the promising (risk-associated) SNPs. In comparison with the low-risk group (fewer than three unfavorable genotypes), the medium-risk group (three unfavorable genotypes) had a 2.00-fold (95% CI=1.31-3.08) increased risk and the high-risk group (more than three unfavorable genotypes) had a 3.14-fold (95% CI=2.03-4.85) increased risk (P for trend < 0.0001). Results for the risk of esophageal adenocarcinoma were similar to the overall risk results. The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.
doi:10.1158/1940-6207.CAPR-08-0135
PMCID: PMC2768267  PMID: 19138993
microRNA; polymorphism; esophageal cancer

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