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author:("Yang, huashan")
1.  Network-based stratification analysis of 13 major cancer types using mutations in panels of cancer genes 
BMC Genomics  2015;16(Suppl 7):S7.
Cancers are complex diseases with heterogeneous genetic causes and clinical outcomes. It is critical to classify patients into subtypes and associate the subtypes with clinical outcomes for better prognosis and treatment. Large-scale studies have comprehensively identified somatic mutations across multiple tumor types, providing rich datasets for classifying patients based on genomic mutations. One challenge associated with this task is that mutations are rarely shared across patients. Network-based stratification (NBS) approaches have been proposed to overcome this challenge and used to classify tumors based on exome-level mutations. In routine research and clinical applications, however, usually only a small panel of pre-selected genes is screened for mutations. It is unknown whether such small panels are effective in classifying patients into clinically meaningful subtypes.
In this study, we applied NBS to 13 major cancer types with exome-level mutation data and compared the classification based on the full exome data with those focusing only on small sets of genes. Specifically, we investigated three panels, FoundationOne (240 genes), PanCan (127 genes) and TruSeq (48 genes). We showed that small panels not only are effective in clustering tumors but also often outperform full exome data for most cancer types. We further associated subtypes with clinical data and identified 5 tumor types (CRC-Colorectal carcinoma, HNSC-Head and neck squamous cell carcinoma, KIRC-Kidney renal clear cell carcinoma, LUAD-Lung adenocarcinoma and UCEC-Uterine corpus endometrial carcinoma) whose subtypes are significantly associated with overall survival, all based on small panels.
Our analyses indicate that effective patient subtyping can be carried out using mutations detected in smaller gene panels, probably due to the enrichment of clinically important genes in such panels.
PMCID: PMC4474538  PMID: 26099277
tumor somatic mutations; networks; subtyping; network-based-stratification
2.  Polymorphisms in Genes of Tricarboxylic Acid Cycle Key Enzymes Are Associated with Early Recurrence of Hepatocellular Carcinoma 
PLoS ONE  2015;10(4):e0124471.
Alterations of activity and expression in tricarboxylic acid (TCA) cycle key enzymes have been indicated in several malignancies, including hepatocellular carcinoma (HCC). They play an important role in the progression of cancer. However, the impact of single nucleotide polymorphisms (SNPs) in genes encoding these key enzymes on the recurrence of HCC has not been investigated. In this study, we genotyped 17 SNPs in genes encoding TCA cycle key enzymes and analyzed their association with recurrence-free survival (RFS) in a cohort of 492 Chinese HCC patients by Cox proportional hazard model and survival tree analysis. We identified 7 SNPs in SDHC, SDHD, FH, and IDH2 genes to be significantly associated with the RFS of HCC patients. Moreover, all these SNPs were associated with the early recurrence (within 2 years after surgery) risk of diseases. Cumulative effect analysis showed that these SNPs exhibited a dose-dependent effect on the overall and early recurrence. Further stratified analysis suggested that number of risk genotypes modified the protective effect on HCC recurrence conferred by transcatheter arterial chemoembolization treatment. Finally, the survival tree analysis revealed that SNP rs10789859 in SDHD gene was the primary factor contributing to HCC recurrence in our population. To the best of our knowledge, we for the first time observed the association between SNPs in genes encoding TCA cycle key enzymes and HCC recurrence risk. Further observational and functional studies are needed to validate our findings and generalize its clinical usage.
PMCID: PMC4404327  PMID: 25894340
3.  Association of leukocyte mitochondrial DNA content with glioma risk: evidence from a Chinese case–control study 
BMC Cancer  2014;14:680.
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
4.  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
5.  Genetic variations in colorectal cancer risk and clinical outcome 
Colorectal cancer (CRC) has an apparent hereditary component, as evidenced by the well-characterized genetic syndromes and family history associated with the increased risk of this disease. However, in a large fraction of CRC cases, no known genetic syndrome or family history can be identified, suggesting the presence of “missing heritability” in CRC etiology. The genome-wide association study (GWAS) platform has led to the identification of multiple replicable common genetic variants associated with CRC risk. These newly discovered genetic variations might account for a portion of the missing heritability. Here, we summarize the recent GWASs related to newly identified genetic variants associated with CRC risk and clinical outcome. The findings from these studies suggest that there is a lack of understanding of the mechanism of many single nucleotide polymorphisms (SNPs) that are associated with CRC. In addition, the utility of SNPs as prognostic markers of CRC in clinical settings remains to be further assessed. Finally, the currently validated SNPs explain only a small fraction of total heritability in complex-trait diseases like CRC. Thus, the “missing heritability” still needs to be explored further. Future epidemiological and functional investigations of these variants will add to our understanding of CRC pathogenesis, and may ultimately lead to individualized strategies for prevention and treatment of CRC.
PMCID: PMC3989953  PMID: 24764655
Colorectal cancer; Genome-wide association study; Single nucleotide polymorphism; Signal transduction pathways; Cell cycle control; Gene desert; Genome instability
6.  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.
PMCID: PMC3955084  PMID: 21292633
HNSCC; SPT; single nucleotide polymorphisms; retinoids
7.  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)
8.  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
9.  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
10.  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
11.  Prostate cancer biomarker: a key field to explore 
Asian Journal of Andrology  2013;15(3):358-359.
PMCID: PMC3739636  PMID: 23435472
12.  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
13.  Profiling HBV integrations in hepatocellular carcinoma 
PMCID: PMC3924654  PMID: 24570928
14.  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
15.  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
16.  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.
PMCID: PMC3477817  PMID: 17582598
ATM; polymorphism; haplotype; diplotype; NSCLC
17.  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
18.  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
19.  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.
PMCID: PMC3105587  PMID: 20819778
20.  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.
PMCID: PMC2950933  PMID: 20627871
21.  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.
PMCID: PMC2955764  PMID: 20858759
sonic hedgehog pathway; cancer risk; recurrence; BCG; non-muscle invasive bladder cancer
22.  A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci 
Rothman, Nathaniel | Garcia-Closas, Montserrat | Chatterjee, Nilanjan | Malats, Nuria | Wu, Xifeng | Figueroa, Jonine | Real, Francisco X | Van Den Berg, David | Matullo, Giuseppe | Baris, Dalsu | Thun, Michael | Kiemeney, Lambertus A | Vineis, Paolo | De Vivo, Immaculata | Albanes, Demetrius | Purdue, Mark P | Rafnar, Thorunn | Hildebrandt, Michelle A T | Kiltie, Anne E | Cussenot, Olivier | Golka, Klaus | Kumar, Rajiv | Taylor, Jack A | Mayordomo, Jose I | Jacobs, Kevin B | Kogevinas, Manolis | Hutchinson, Amy | Wang, Zhaoming | Fu, Yi-Ping | Prokunina-Olsson, Ludmila | Burdette, Laurie | Yeager, Meredith | Wheeler, William | Tardón, Adonina | Serra, Consol | Carrato, Alfredo | García-Closas, Reina | Lloreta, Josep | Johnson, Alison | Schwenn, Molly | Karagas, Margaret R | Schned, Alan | Andriole, Gerald | Grubb, Robert | Black, Amanda | Jacobs, Eric J | Diver, W Ryan | Gapstur, Susan M | Weinstein, Stephanie J | Virtamo, Jarmo | Cortessis, Victoria K | Gago-Dominguez, Manuela | Pike, Malcolm C | Stern, Mariana C | Yuan, Jian-Min | Hunter, David | McGrath, Monica | Dinney, Colin P | Czerniak, Bogdan | Chen, Meng | Yang, Hushan | Vermeulen, Sita H | Aben, Katja K | Witjes, J Alfred | Makkinje, Remco R | Sulem, Patrick | Besenbacher, Soren | Stefansson, Kari | Riboli, Elio | Brennan, Paul | Panico, Salvatore | Navarro, Carmen | Allen, Naomi E | Bueno-de-Mesquita, H Bas | Trichopoulos, Dimitrios | Caporaso, Neil | Landi, Maria Teresa | Canzian, Federico | Ljungberg, Borje | Tjonneland, Anne | Clavel-Chapelon, Francoise | Bishop, David T | Teo, Mark T W | Knowles, Margaret A | Guarrera, Simonetta | Polidoro, Silvia | Ricceri, Fulvio | Sacerdote, Carlotta | Allione, Alessandra | Cancel-Tassin, Geraldine | Selinski, Silvia | Hengstler, Jan G | Dietrich, Holger | Fletcher, Tony | Rudnai, Peter | Gurzau, Eugen | Koppova, Kvetoslava | Bolick, Sophia C E | Godfrey, Ashley | Xu, Zongli | Sanz-Velez, José I | García-Prats, María D | Sanchez, Manuel | Valdivia, Gabriel | Porru, Stefano | Benhamou, Simone | Hoover, Robert N | Fraumeni, Joseph F | Silverman, Debra T | Chanock, Stephen J
Nature genetics  2010;42(11):978-984.
We conducted a multi-stage, genome-wide association study (GWAS) of bladder cancer with a primary scan of 589,299 single nucleotide polymorphisms (SNPs) in 3,532 cases and 5,120 controls of European descent (5 studies) followed by a replication strategy, which included 8,381 cases and 48,275 controls (16 studies). In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1; rs1014971, (P=8×10−12) maps to a non-genic region of chromosome 22q13.1; rs8102137 (P=2×10−11) on 19q12 maps to CCNE1; and rs11892031 (P=1×10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previous GWAS associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P=4×10−11) and a tag SNP for NAT2 acetylation status (P=4×10−11), as well as demonstrated smoking interactions with both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into mechanisms of carcinogenesis.
PMCID: PMC3049891  PMID: 20972438
23.  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.
PMCID: PMC2792319  PMID: 19875696
24.  Genome-wide profiling of chromosomal alterations in renal cell carcinoma using high-density single nucleotide polymorphism arrays 
The identification of genetic aberrations may help understand the mechanisms of tumorigenesis and has important implications in diagnosis, prognosis, and treatment.
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.
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.
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.
PMCID: PMC2768265  PMID: 19521957
25.  Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large Scale Evaluation of Genetic Variants 
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.
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.
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.
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.
PMCID: PMC2964280  PMID: 19584075
iSelect Infinium; Single nucleotide polymorphisms; Head and neck cancer; Secondary primary tumor; recurrence

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