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author:("Xu, jinfeng")
1.  Epidermal growth factor receptor pathway polymorphisms and the prognosis of hepatocellular carcinoma 
The EGFR signaling pathway is important in the control of vital processes in the carcinogenesis of hepatocellular carcinoma (HCC), including cell survival, cell cycle progression, tumor invasion and angiogenesis. In the current study, we aim to assess if genetic variants in the genes of the EGFR signaling pathway are associated with the prognosis of HCC. We genotyped 36 single nucleotide polymorphisms (SNP) in four core genes (EGF, EGFR, VEGF, and VEGFR2) by using DNA from blood samples of 363 HCC patients with surgical resection. The associations between genotypes and overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confident intervals (CIs) were estimated for the multivariate survival analyses by Cox proportional hazards regression models, adjusting for age, gender, family history, HBsAg and AFP. We found that five SNPs in the VEGFR2 gene were significantly associated with clinical outcomes of HCC patients. Among them, four SNPs (rs7692791, rs2305948, rs13109660, rs6838752) were associated with OS (p=0.035, 0.038, 0.029 and 0.028, respectively), and two SNPs (rs7692791 and rs2034965) were associated with DFS (p=0.039 and 0.017, respectively). Particularly, rs7692791 TT genotype was associated with both reduced OS (p=0.037) and DFS (p=0.043). However, only one SNP rs2034965 with the AA genotype was shown to be an independent effect on DFS (p=0.009) in the multivariate analysis. None of the other 31 polymorphisms or 9 haplotypes attained from the four genes was significantly associated with OS or DFS. Our results illustrated the potential use of VEGFR2 polymorphisms as prognostic markers for HCC patients.
PMCID: PMC4300692  PMID: 25628948
Hepatocellular carcinoma; survival; EGF; EGFR; VEGF; VEGFR2; genetic polymorphisms
2.  Plateau Effect of Prostate Cancer Risk-Associated SNPs in Discriminating Prostate Biopsy Outcomes 
The Prostate  2013;73(16):1824-1835.
Additional prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) continue to be identified. It is unclear whether addition of newly identified SNPs improves the discriminative performance of biopsy outcomes over previously established SNPs.
A total of 667 consecutive patients that underwent prostate biopsy for detection of PCa at Huashan Hospital and Changhai Hospital, Shanghai, China were recruited. Genetic scores were calculated for each patient using various combinations of 29 PCa risk-associated SNPs. Performance of these genetic scores for discriminating prostate biopsy outcomes were compared using the area under a receiver operating characteristic curve (AUC).
The discriminative performance of genetic score derived from a panel of all 29 SNPs (24 previous and 5 new) was similar to that derived from the 24 previously established SNPs, the AUC of which were 0.60 and 0.61, respectively (P = 0.72). When SNPs with the strongest effect on PCa risk (ranked based on contribution to the total genetic variance from an external study) were sequentially added to the models for calculating genetic score, the AUC gradually increased and peaked at 0.62 with the top 13 strongest SNPs. Under the 13-SNP model, the PCa detection rate was 21.52%, 36.74%, and 51.98%, respectively for men with low (<0.5), intermediate (0.5–1.5), and high (>1.5) genetic score, P-trend = 9.91 × 10−6.
Genetic score based on PCa risk-associated SNPs implicated to date is a significant predictor of biopsy outcome. Additional small-effect PCa risk-associated SNPs to be discovered in the future are unlikely to further improve predictive performance.
PMCID: PMC3910089  PMID: 24037738
prostate; SNPs; genetic score; ChinaPCa; biopsy; AUC
3.  Evaluation of Reported Prostate Cancer Risk-Associated SNPs From Genome-Wide Association Studies of Various Racial Populations in Chinese Men 
The Prostate  2013;73(15):1623-1635.
Several genome-wide association studies (GWAS) of prostate cancer (PCa) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with PCa risk in various racial groups. The objective of this study is to evaluate which of these SNPs are associated with PCa risk in Chinese men and estimate their strength of association.
All SNPs that were reported to be associated with PCa risk in GWAS from populations of European, African American, Japanese, and Chinese descent were evaluated in 1,922 PCa cases and 2,175 controls selected from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). A logistic regression analysis was used to estimate allelic odds ratios (ORs) of these SNPs for PCa.
Among the 53 SNPs, 50 were polymorphic in the Chinese population. Of which, 10 and 24 SNPs were significantly associated with PCa risk in Chinese men at P < 0.001 and <0.05, respectively. These 24 significant SNPs included 17, 5, and 2 SNPs that were originally discovered in European, Japanese, and Chinese descent, respectively. The estimated ORs ranged from 1.10 to 1.49 and the direction of association was consistent with previous studies. When ORs were estimated separately for PCa with Gleason score ≤7 and ≥8, a marginally significant difference in ORs was found only for two of the 24 SNPs (P = 0.02 and 0.04).
About half of PCa risk-associated SNPs identified in GWAS of various populations are associated with PCa risk in Chinese men. Information on PCa risk-associated SNPs and their ORs may facilitate risk assessment of PCa risk in Chinese men.
PMCID: PMC3928594  PMID: 24038036
prostate cancer; SNPs; genome-wide association; Chinese
4.  Prediction of Prostate Cancer From Prostate Biopsy in Chinese Men Using a Genetic Score Derived From 24 Prostate Cancer Risk-Associated SNPs 
The Prostate  2013;73(15):1651-1659.
Twenty-four prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) in Chinese men have been cataloged. We evaluated whether these SNPs can independently predict outcomes of prostate biopsy, and improve the predictive performance of existing clinical variables.
Three hundred eight consecutive patients that underwent prostate biopsy for detection of PCa at Huashan Hospital, Shanghai, China between April 2011 and August 2012 were recruited. Clinical variables such as serum prostate-specific antigen (PSA) levels and peripheral blood samples were collected prior to a 10-core biopsy. A genetic score based on these 24 PCa associated SNPs was calculated for each individual.
Among 308 patients underwent prostate biopsy, 141 (45.8%) were diagnosed with PCa. Genetic score was significantly higher in patients with PCa (median = 1.30) than without (median = 0.89), P = 3.81 × 10−6. The difference remained significant after adjusting for age and total PSA, P = 0.007. The PCa detection rate increased with increasing genetic score; 26.3%, 43.2%, and 60.0% for men with lower (<0.5), average (0.5–1.5), and higher (>1.5) genetic score, respectively, P−trend = 0.0003. For patients with moderately elevated PSA levels (1.6–20 ng/ml), the PCa detection rate was 31.2% overall and was 16.7%, 31.2%, and 40.9% for men with lower (<0.5), average (0.5–1.5), and higher (>1.5) genetic score, respectively, P−trend = 0.03. For patients with PSA 2: 20 ng/ml, however, the PCa detection rates were high (>69%) regardless of genetic score.
A genetic score based on PCa risk-associated SNPs is an independent predictor of prostate biopsy outcomes in Chinese men and may be helpful to determine the need for prostate biopsy among patients within a ‘‘gray zone’’ of PCa risk.
PMCID: PMC3909876  PMID: 23868750
ChinaPCa; SNPs; risk assessment; PSA
5.  Polymorphisms of an Innate Immune Gene, Toll-Like Receptor 4, and Aggressive Prostate Cancer Risk: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(10):e110569.
Toll-like receptor 4 (TLR4) is one of the best known TLR members expressed on the surface of several leukocytes and tissue cells and has a key function in detecting pathogen and danger-associated molecular patterns. The role of TLR4 in the pathophysiology of several age-related diseases is also well recognized, such as prostate cancer (PCa). TLR4 polymorphisms have been related to PCa risk, but the relationship between TLR4 genotypes and aggressive PCa risk has not been evaluated by any systematic reviews.
We performed a systematic review and meta-analysis of candidate-gene and genome-wide association studies analyzing this relationship and included only white population. Considering appropriate criteria, only nine studies were analyzed in the meta-analysis, including 3,937 aggressive PCa and 7,382 controls.
Using random effects model, no significant association was found in the ten TLR4 SNPs reported by at least four included studies under any inheritance model (rs2737191, rs1927914, rs10759932, rs1927911, rs11536879, rs2149356, rs4986790, rs11536889, rs7873784, and rs1554973). Pooled estimates from another ten TLR4 SNPs reported by three studies also showed no significant association (rs10759930, rs10116253, rs11536869, rs5030717, rs4986791, rs11536897, rs1927906, rs913930, rs1927905, and rs7045953). Meta-regression revealed that study type was not a significant source of between-study heterogeneity.
TLR4 polymorphisms were not significantly associated with the risk of aggressive PCa.
PMCID: PMC4215920  PMID: 25360682
6.  miRNA-130b is required for the ERK/FOXM1 pathway activation-mediated protective effects of isosorbide dinitrate against mesenchymal stem cell senescence induced by high glucose 
The present study was carried out to investigate the hypothesis that organic nitrates can attenuate the senescence of mesenchymal stem cells (MSCs), a superior cell source involved in the regeneration and repair of damaged tissue. MSCs were treated with high glucose (HG) in order to induce senescence, which was markedly attenuated by pre-treatment with isosorbide dinitrate (ISDN), a commonly used nitrate, as indicated by senescence-associated galactosidase (SA-β-gal) activity, p21 expression, as well as by the mRNA levels of DNA methyltransferase 1 (DNMT1) and differentiated embryo chondrocyte expressed gene 1 (DEC1), which are senescence-related biomarkers. It was also found that the senescent MSCs (induced by HG glucose) exhibited a marked downregulation in ERK activity and forkhead box M1 (FOXM1) expression, which was reversed by ISDN preconditioning. Of note, the inhibition of ERK phosphorylation or the downregulation of FOXM1 statistically abolished the favourable effects of ISDN. In addition, the investigation of the senescence-associated miR-130 family suggested that miR-130b mediates the beneficial effects of ISDN; it was found that the protective effects of ISDN against the senescence of MSCs were prominently reversed by the knockdown of miR-130b. Furthermore, the downregulation of ERK phosphorylation or FOXM1 expression decreased the miR-130b expression level; however, the suppression of miR-130b demonstrated no significant impact on ERK phosphorylation or FOXM1 expression. Taken together, to the best of our knowledge, the present study is the first to demonstrate the favourable effects of ISDN against HG-induced MSC senescence, which are mediated through the activation of the ERK/FOXM1 pathway and the upregulation of miR-130b.
PMCID: PMC4249746  PMID: 25355277
mesenchymal stem cell; senescence; hyperglycemia; nitrate; mechanism
7.  Immunization Associated with Erectile Dysfunction Based on Cross-Sectional and Genetic Analyses 
PLoS ONE  2014;9(10):e111269.
Erectile dysfunction (ED) is a global disease affecting a large number of people. Some studies have found a relationship between low-grade inflammation and ED. We hypothesized that the immune system might play a key role in the outcome of ED. Five immune agents (C3, C4, IgA, IgM, and IgG) were collected based on the Fangchenggang Area Male Health and Examination Survey (FAMHES), using methods of a traditional cross-sectional analysis. Our results repeated the significant association between ED and metabolic syndrome, obesity, and so forth. However, there seemed to be no positive relation between the tested indexes and ED risk in the baseline analysis (C3: P = 0.737; C4: P = 0.274; IgA: P = 0.943; IgG: P = 0.069; IgM: P = 0.985). Then, after adjusting for age and multivariate covariates, a potentially significant association between ED and IgG was discovered (P = 0.025 and P = 0.034, respectively). Meanwhile, in order to describe the development of ED on a gene level, SNP–set kernel-machine association test (SKAT) was applied with the known humoral immune genes involved. The outcomes suggested that PTAFR (binary P value: 0.0096; continuous P value: 0.00869), IL27 (0.0029; 0.1954), CD37 (0.0248; 0.5196), CD40 (0.7146; 0.0413), IL7R (0.1223; 0.0222), PSMB9 (0.1237; 0.0212), and CXCR3 (0.0849; 0.0478) might be key genes in ED, especially IL27, when we restricted the family-wise error rate (FWER) to 0.5. Our study shows that IgG and seven genes (PTAFR, CD37, CD40, IL7R, PSMB9, CXCR3, and especially IL27) might be key factors in the pathogenesis of ED, which could pave the way for future gene and immune therapies.
PMCID: PMC4208848  PMID: 25343742
8.  Isolation of myeloid-derived suppressor cells subsets from spleens of orthotopic liver cancer-bearing mice by fluorescent-activated and magnetic-activated cell sorting: similarities and differences 
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that commonly expand during tumor development and that play a critical role in suppression of immune responses. MDSCs can be classified into two groups: Mo-MDSCs and G-MDSCs. These cells differ in their morphology, phenotype, differentiation ability, and immunosuppressive activity, and inhibit immune responses via different mechanisms. Therefore, identifying an effective method for isolating viable Mo-MDSCs and G-MDSCs is important. Here, we demonstrated the differences and similarities between fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS) in sorting G-MDSCs and Mo-MDSCs. Both MACS and FACS could obtain G-MDSCs and Mo-MDSCs with high viability and purity. A high yield and purity of G-MDSCs could be obtained both by using FACS and MACS, because G-MDSCs are highly expressed in the spleen of tumor-bearing mice. However, Mo-MDSCs, which comprise a small population among leukocytes, when sorted by MACS, could be obtained at much greater cell number, although with a slightly lower purity, than when sorted by FACS. In conclusion, we recommended using both FACS and MACS for isolating G-MDSCs, and using MACS for isolation of Mo-MDSCs.
PMCID: PMC4270530  PMID: 25550790
Fluorescent-activated cell sorting (FACS); granulocytic; magnetic-activated cell sorting (MACS); monocytic; myeloid-derived suppressor cell; separation
9.  Comparison of clinical outcomes and genomic characteristics of single focus and multifocal glioblastoma 
Journal of neuro-oncology  2014;119(2):429-435.
We investigate the differences in molecular signature and clinical outcomes between multiple lesion glioblastoma (GBM) and single focus GBM in the modern treatment era. Between August 2000 and May 2010, 161 patients with GBM were treated with modern radiotherapy techniques. Of this group, 33 were considered to have multiple lesion GBM (25 multifocal and 8 multicentric). Patterns of failure, time to progression and overall survival were compared based on whether the tumor was considered a single focus or multiple lesion GBM. Genomic groupings and methylation status were also investigated as a possible predictor of multifocality in a cohort of 41 patients with available tissue for analysis. There was no statistically significant difference in overall survival (p < 0.3) between the multiple lesion tumors (8.2 months) and single focus GBM (11 months). Progression free survival was superior in the single focus tumors (7.1 months) as compared to multi-focal (5.6 months, p = 0.02). For patients with single focus, multifocal and multicentric GBM, 81, 76 and 88 % of treatment failures occurred in the 60 Gy volume (p < 0.5), while 54, 72, and 38 % of treatment failures occurred in the 46 Gy volume (p < 0.4). Out of field failures were rare in both single focus and multiple foci GBM (7 vs 3 %). Genomic groupings and methylation status were not found to predict for multifocality. Patterns of failure, survival and genomic signatures for multiple lesion GBM do not appreciably differ when compared to single focus tumors.
PMCID: PMC4146694  PMID: 24990827
Glioblastoma; Multifocal; Multicentric
Cell  2013;155(1):200-214.
Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The co-repressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that de-repression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for pro-inflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin sensitizing therapies.
PMCID: PMC4131699  PMID: 24074869
nuclear co-repressor; insulin resistance; obesity; macrophage; inflammation
11.  Genome-Wide Association Study Identifies Variants in PMS1 Associated with Serum Ferritin in a Chinese Population 
PLoS ONE  2014;9(8):e105844.
Only a small proportion of genetic variation in serum ferritin has been explained by variant genetic studies, and genome-wide association study (GWAS) for serum ferritin has not been investigated widely in Chinese population. We aimed at exploring the novel genetic susceptibility to serum ferritin, and performed this two stage GWAS in a healthy Chinese population of 3,495 men aged 20–69 y, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals in the second stage. Serum ferritin was measured with electrochemiluminescence immunoassay, and DNA samples were collected for genotyping. A total of 1,940,243 SNPs were tested by using multivariate linear regression analysis. After adjusting for population stratification, age and BMI, the rs5742933 located in the 5′UTR region of PMS1 gene on chromosome 2 was the most significantly associated with ferritin concentrations (P-combined = 2.329×10−10) (β = −0.11, 95% CI: −0.14, −0.07). Moreover, this marker was about 200kb away from the candidate gene SLC40A1 which is responsible for iron export. PMS1 gene was the novel genetic susceptibility to serum ferritin in Chinese males and its relation to SLC40A1 needs further study.
PMCID: PMC4146590  PMID: 25162662
12.  Neuroglobin Overexpression Inhibits Oxygen-Glucose Deprivation-induced Mitochondrial Permeability Transition Pore Opening in Primary Cultured Mouse Cortical Neurons 
Neurobiology of disease  2013;0:95-103.
Neuroglobin (Ngb) is an endogenous neuroprotective molecule against hypoxic/ischemic brain injury, but the underlying mechanisms remain largely undefined. Our recent study revealed that Ngb can bind to voltage-dependent anion channel (VDAC), a regulator of mitochondria permeability transition (MPT). In this study we examined the role of Ngb in MPT pore (mPTP) opening following oxygen-glucose deprivation (OGD) in primary cultured mouse cortical neurons. Co-immunoprecipitation (Co-IP) and immuocytochemistry showed that the binding between Ngb and VDAC was increased after OGD compared to normoxia, indicating the OGD-enhanced Ngb-VDAC interaction. Ngb overexpression protected primary mouse cortical neurons from OGD-induced neuronal death, to an extent comparable to mPTP opening inhibitor, cyclosporine A (CsA) pretreatment. We further measured the role of Ngb in OGD-induced mPTP opening using Ngb overexpression and knockdown approaches in primary cultured neurons, and recombinant Ngb exposure to isolated mitochondria. Same as CsA pretreatment, Ngb overexpression significantly reduced OGD-induced mPTP opening markers including mitochondria swelling, mitochondrial NAD+ release, and cytochrome c (Cyt c) release in primary cultured neurons. Recombinant Ngb incubation significantly reduced OGD-induced NAD+ release and Cyt c release from isolated mitochondria. In contrast, Ngb knockdown significantly increased OGD-induced neuron death, and increased OGD-induced mitochondrial NAD+ release and Cyt c release as well, and these outcomes could be rescued by CsA pretreatment. In summary, our results demonstrated that Ngb overexpression can inhibit OGD-induced mPTP opening in primary cultured mouse cortical neurons, which may be one of the molecular mechanisms of Ngb's neuroprotection.
PMCID: PMC3674158  PMID: 23639789
13.  Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4 
Nature genetics  2012;44(11):1231-1235.
Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.
PMCID: PMC4116636  PMID: 23023329
14.  Association of Prostate-Specific Antigen Promoter Genotype with Clinical and Histopathologic Features of Prostate Cancer 
The serum test for the secreted protease prostate-specific antigen (PSA) is the most widely used screening tool for prostate cancer. The PSA gene contains multiple functional and nonfunctional single nucleotide polymorphisms (SNP) in its promoter. We showed previously that the rs925013 G/A SNP, but not the rs266882 G/A SNP, was significantly associated with serum PSA in healthy men. In this study, we evaluated the association of the PSA promoter genotype with clinical data in a cohort of 1,224 men with prostate cancer. Previous work with a subset of this cohort has shown that percent high-grade (Gleason grades 4 and 5) cancer was the strongest predictor of biochemical recurrence (PSA relapse). We found a statistically significant association (P < 0.05) of the rs925013 SNP with several clinical and histomorphologic variables. The G allele was associated with higher serum PSA at diagnosis, higher percent Gleason grade 3 cancer, and lower percent high-grade and Gleason grade 4 cancer. The rs266882 SNP was modestly associated with PSA at diagnosis in a dominant model but was not associated with cancer grade. Neither SNP was associated with biochemical recurrence. The statistically significant predictors of biochemical recurrence were tumor location in the peripheral zone [odds ratio (OR), 10.71; 95% confidence interval (95% CI), 3.15-36.49], presence of any Gleason grade 4/5 cancer (OR, 4.26; 95% CI, 1.30-14.00), presence of any intraductal cancer (OR, 1.03; 95% CI, 1.00-1.04), and serum PSA at diagnosis (OR, 2.04; 95% CI, 1.50-2.77).
PMCID: PMC4114034  PMID: 18768516
15.  Genetic variants in STAT4 and HLA-DQ genes confer risk of hepatitis B virus–related hepatocellular carcinoma 
Nature genetics  2012;45(1):72-75.
To identify genetic susceptibility loci for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Chinese population, we carried out a genome-wide association study (GWAS) in 2,514 chronic HBV carriers (1,161 HCC cases and 1,353 controls) followed by a 2-stage validation among 6 independent populations of chronic HBV carriers (4,319 cases and 4,966 controls). The joint analyses showed that HCC risk was significantly associated with two independent loci: rs7574865 at STAT4, Pmeta = 2.48 × 10−10, odds ratio (OR) = 1.21; and rs9275319 at HLA-DQ, Pmeta = 2.72 × 10−17, OR = 1.49. The risk allele G at rs7574865 was significantly associated with lower mRNA levels of STAT4 in both the HCC tissues and nontumor tissues of 155 individuals with HBV-related HCC (Ptrend = 0.0008 and 0.0002, respectively). We also found significantly lower mRNA expression of STAT4 in HCC tumor tissues compared with paired adjacent nontumor tissues (P = 2.33 × 10−14).
PMCID: PMC4105840  PMID: 23242368
16.  Comparative Effectiveness Research in Cancer Genomics and Precision Medicine: Current Landscape and Future Prospects 
A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the “real-world” effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling.
PMCID: PMC3699435  PMID: 23661804
17.  Genetic markers associated with early cancer-specific mortality following prostatectomy 
Cancer  2013;119(13):10.1002/cncr.27954.
To identify novel effectors and markers of localized but potentially life-threatening prostate cancer (PCa), we evaluated chromosomal copy number alterations (CNAs) in tumors from patients who underwent prostatectomy and correlated these with clinicopathologic features and outcome.
CNAs in tumor DNAs from 125 prostatectomy patients in the discovery cohort were assayed with high resolution Affymetrix 6.0 SNP microarrays and then analyzed using the Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm.
The assays revealed twenty significant regions of CNAs, four of them novel, and identified the target genes of four of the alterations. By univariate analysis, seven CNAs were significantly associated with early PCa-specific mortality. These included gains of chromosomal regions that contain the genes MYC, ADAR, or TPD52 and losses of sequences that incorporate SERPINB5, USP10, PTEN, or TP53. On multivariate analysis, only the CNAs of PTEN and MYC contributed additional prognostic information independent of that provided by pathologic stage, Gleason score, and initial PSA level. Patients whose tumors had alterations of both genes had a markedly elevated risk of PCa-specific mortality (OR = 53; C.I.= 6.92–405, P = 1 × 10−4). Analyses of 333 tumors from three additional distinct patient cohorts confirmed the relationship between CNAs of PTEN and MYC and lethal PCa.
This study identified new CNAs and genes that likely contribute to the pathogenesis of localized PCa and suggests that patients whose tumors have acquired CNAs of PTEN, MYC, or both have an increased risk of early PCa-specific mortality.
PMCID: PMC3863778  PMID: 23609948
prostate cancer death; PTEN; MYC; somatic DNA copy number
18.  Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk 
Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk.
In a case-cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis.
After adjusting for significant covariates – including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin – relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [hazard ratios comparing extreme quartiles (HRQ4-Q1) for sIL-6R = 0.56, 95% CI = 0.38–0.83; HRQ4-Q1 for sIL-1R2 = 0.44, 95% CI = 0.29–0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw.
High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease.
sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.
PMCID: PMC3947182  PMID: 24192010
soluble cytokine receptor; receptor antagonist; colorectal cancer; IL-1; IL-6; TNF
19.  The Xu's chart for prostate biopsy: a visual presentation of the added value of biomarkers to prostate-specific antigen for estimating detection rates of prostate cancer 
Asian Journal of Andrology  2014;16(4):536-540.
Elevated serum prostate-specific antigen (PSA) level is the primary indication for prostate biopsy for detection of prostate cancer (PCa) in the modern era. The detection rate of PCa from biopsy is typically below 30%, especially among patients with PSA levels at 4–10 ng ml−1. In the past several years, additional biomarkers, such as Prostate Health Index, PCA3 and genetic risk score (GRS) derived from multiple PCa risk-associated single nucleotide polymorphisms (SNPs) have been shown to provide added value to PSA in discriminating prostate biopsy outcomes. However, the adoption rate of these novel biomarkers in clinics is low, largely due to poor understanding of the added value of novel biomarkers. To address this matter, we developed a chart to visually present (i) expected detection rates of PCa from biopsy with respect to PSA levels, and more importantly, (ii) a range of PCa detection rates at the same PSA levels when novel biomarkers are considered. This chart, called the Xu's chart for prostate biopsy, is not a formal risk prediction model; rather, a simple visual tool for urologists to communicate with their patients an initial evaluation of PCa detection rate based on their PSA levels and a possible recommendation for additional biomarkers. A more comprehensive evaluation of PCa risk using existing risk assessment tools such as nomograms can be followed once additional biomarkers are measured. The current version of the chart is only a prototype and should be further developed to include the detection rate of aggressive PCa, and validated in larger studies.
PMCID: PMC4104076  PMID: 24625885
20.  Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation 
Nature chemistry  2013;5(5):383-389.
The recent synthesis of pyrimidine ribonucleoside-2′,3′-cyclic phosphates under prebiotically plausible conditions has strengthened the case for the involvement of RNA at an early stage in the origin of life. However, a prebiotic conversion of these weakly activated monomers, and their purine counterparts, to the 3′,5′-linked RNA polymers of extant biochemistry has been lacking – previous attempts leading only to short oligomers with mixed linkages. Here we show that the 2′-hydroxyl group of oligoribonucleotide-3′-phosphates can be chemoselectively acetylated in water under prebiotically credible conditions, allowing rapid and efficient template-directed ligation. The 2′-O-acetyl group at the ligation junction of the product RNA strand can be removed under conditions that leave the internucleotide bonds intact. Remarkably, acetylation of mixed oligomers possessing either 2′- or 3′-terminal phosphates is selective for the 2′-hydroxyl group of the latter. This newly discovered chemistry thus suggests a prebiotic route from ribonucleoside-2′,3′-cyclic phosphates to predominantly 3′,5′-linked RNA via partially 2′-O-acetylated-RNA.
PMCID: PMC4074891  PMID: 23609088
21.  Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China 
PLoS ONE  2014;9(6):e97923.
Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications.
Methods and Findings
Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023).
We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China.
PMCID: PMC4062418  PMID: 24941225
22.  The G84E mutation of HOXB13 is associated with increased risk for prostate cancer: results from the REDUCE trial 
Carcinogenesis  2013;34(6):1260-1264.
A novel rare mutation, homeobox B13 (HOXB13) G84E, was reported to co-segregate with prostate cancer (PCa) in hereditary PCa families and associate with PCa risk in unrelated cases and controls. In this study, we aim to compare the G84E mutation frequency among subjects of different races/ethnicities from various geographic regions in the world and to assess its risk for developing PCa, in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. All the 3508 subjects had initial negative prostate biopsy and were biopsied at Year 2 and 4 for detection of PCa. The G84E mutation was detected only in Caucasians, with the highest carrier frequency in Northern Europe (1.06%), followed by Western Europe (0.60%) and North America (0.31%). No mutation carrier was observed in Southern Europe, Eastern Europe, Latin America, Australia and South Africa. In Caucasians, the G84E mutation frequency was 0.99% and 0.24% in positive and negative biopsy subjects, respectively (P = 0.01). In positive biopsy subjects, the frequency was significantly higher in subjects with a positive family history than those without (4.31% versus 0.34%, P = 0.002). In the 4 year follow-up, the PCa detection rate was 53.8% among the 13 mutation carriers and 22.0% among 3186 non-carriers, relative risk = 2.45 (95% confidence interval: 1.48–4.07). All mutation carriers shared a common haplotype, suggesting a founder effect. In Finland, the G84E mutation was estimated to occur in the year 1792 (95% credible interval: 1735–1831). In conclusion, the G84E mutation of HOXB13, a relatively recent mutation that likely occurred in Northern Europe, significantly increases risk for PCa.
PMCID: PMC3670258  PMID: 23393222
23.  Genome-Wide Association Scan for Variants Associated with Early-Onset Prostate Cancer 
PLoS ONE  2014;9(4):e93436.
Prostate cancer is the most common non-skin cancer and the second leading cause of cancer related mortality for men in the United States. There is strong empirical and epidemiological evidence supporting a stronger role of genetics in early-onset prostate cancer. We performed a genome-wide association scan for early-onset prostate cancer. Novel aspects of this study include the focus on early-onset disease (defined as men with prostate cancer diagnosed before age 56 years) and use of publically available control genotype data from previous genome-wide association studies. We found genome-wide significant (p<5×10−8) evidence for variants at 8q24 and 11p15 and strong supportive evidence for a number of previously reported loci. We found little evidence for individual or systematic inflated association findings resulting from using public controls, demonstrating the utility of using public control data in large-scale genetic association studies of common variants. Taken together, these results demonstrate the importance of established common genetic variants for early-onset prostate cancer and the power of including early-onset prostate cancer cases in genetic association studies.
PMCID: PMC3989171  PMID: 24740154
24.  RNA Sequencing Reveals Upregulation of RUNX1-RUNX1T1 Gene Signatures in Clear Cell Renal Cell Carcinoma 
BioMed Research International  2014;2014:450621.
In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.
PMCID: PMC3982423  PMID: 24783204

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