HCMMD: systematic evaluation of metabolites in body fluids as liquid biopsy biomarker for human cancers.

Metabolomics is a rapidly expanding field in systems biology used to measure alterations of metabolites and identify metabolic biomarkers in response to disease processes. The discovery of metabolic biomarkers can improve early diagnosis, prognostic prediction, and therapeutic intervention for cancers. However, there are currently no databases that provide a comprehensive evaluation of the relationship between metabolites and cancer processes. In this review, we summarize reported metabolites in body fluids across pan-cancers and characterize their clinical applications in liquid biopsy. We conducted a search for metabolic biomarkers using the keywords ("metabolomics" OR "metabolite") AND "cancer" in PubMed. Of the 22,254 articles retrieved, 792 were deemed potentially relevant for further review. Ultimately, we included data from 573,300 samples and 17,083 metabolic biomarkers. We collected information on cancer types, sample size, the human metabolome database (HMDB) ID, metabolic pathway, area under the curve (AUC), sensitivity and specificity of metabolites, sample source, detection method, and clinical features were collected. Finally, we developed a user-friendly online database, the Human Cancer Metabolic Markers Database (HCMMD), which allows users to query, browse, and download metabolite information. In conclusion, HCMMD provides an important resource to assist researchers in reviewing metabolic biomarkers for diagnosis and progression of cancers.

Higher insoluble fiber intake is associated with a lower risk of prostate cancer: results from the PLCO cohort.

Studies regarding the relationship between fiber intake and prostate cancer (PCa) have conflicting results. Therefore, this study examined the relationship between fiber intake and the risk of PCa by using data from Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. A total of 54,336 participants in the United States, consisting of 6,414 patients with PCa, were included in this study. Multivariate Cox regression models were applied to estimate adjusted hazard ratios (aHRs) and corresponding 95% confidence intervals (CIs). Compared with individuals in the lowest quartile, individuals in the highest quartile of insoluble fiber intake had a significantly lower risk of PCa (aHR, 0.87; 95% CI, 0.78-0.98). By contrast, no significant associations were detected between total fiber intake (aHR, 0.90; 95% CI, 0.80-1.01) or soluble fiber intake (aHR, 0.90; 95% CI, 0.80-1.02). Subgroup analyses showed that insoluble fiber was related to a decreased risk of PCa in subjects with the following characteristics: age > 65 years, nonsmoking or former smokers, education level ≤ high school, non-Hispanic white ethnicity, or without a family history of PCa. In addition, significant combined effects of insoluble fiber intake, age and family history of PCa on the risk of PCa were observed, but no combined effects of smoking status and insoluble fiber intake were observed. In addition, total fiber, insoluble fiber, and soluble fiber intake had no influence on the mortality of PCa patients. These results show that all 3 measures of fiber suggest a protective association, but insoluble fiber may have a stronger association with the risk of PCa. Future studies are warranted to further investigate these relationships.

Diagnostic role of plasma ORM2 in differentiating prostate cancer from benign prostatic hyperplasia.

PURPOSE: Markers are needed to increase the diagnostic accuracy of prostate-specific antigen (PSA) in prostate cancer (PCa) screening. Mounting evidence has shown that plasma proteins can be hopeful biomarkers for cancer diagnosis. METHODS: Tandem mass tag (TMT)-based proteomics and parallel reaction monitoring (PRM) analysis were used to screen the differential proteins and further validated in other independent studies (n = 539). Receiver-operating characteristic (ROC), decision curves and nomograms were applied to assess the diagnostic accuracy of biomarkers. RESULTS: Three candidate proteins (DBP, LCAT and ORM2) were preliminarily screened. Subsequent validation studies revealed significant upregulation of ORM2 in PCa patients across other independent cohorts. ORM2 yielded excellent discriminative power for PCa from benign prostatic hyperplasia (BPH) patients (AUC = 0.861 and 0.814 in validation phases 2a and 2b, respectively). Importantly, the combination of ORM2 and PSA gave better predictive accuracy than PSA alone. We incorporated age, PSA and ORM2 into a nomogram, which yielded C-index of 0.883 in validation phase 2a. A similar C-index of 0.879 was obtained in external validation phase 2b. CONCLUSIONS: In summary, our study suggests that ORM2 could be treated as a complementary biomarker for PSA in distinguishing PCa from BPH.

Association of functional genetic variants in TFF1 and nephrolithiasis risk in a Chinese population.

Trefoil Factor 1 (TFF1) is considered to be able to inhibit the formation of kidney stone. However, genetic variants in TFF1 and corresponding function in kidney stone development are still not well studied. In this study, the discovery set including 230 cases and 250 controls was used to analyze the association between seven tagSNPs of TFF1 gene and the nephrolithiasis risk. Further evaluation was confirmed by the validation set comprising 307 cases and 461 controls. The consequences of the two-stage case-control study indicated that individuals with the rs3761376 A allele have significantly increased nephrolithiasis risk than those with the GG genotypes [adjusted odds ratio (OR) = 1.35, 95% confidence interval (CI) = 1.05-1.73]. Moreover, we also carried out a stratified analysis and found the increased nephrolithiasis risks at A allele among males, overweight individuals, no hypertensive individuals, nondiabetic individuals, smokers, and drinkers. In the following functional experiments, the notably lower expression of TFF1 was exhibited by the vectors carrying A allele compared with those carrying G allele in both luciferase (P = 0.022) and expression vectors (P = 0.041). In addition to tissue detection, we confirmed a significant inverse association of rs3761376 G > A and TFF1 gene expression (P < 0.001). These results suggest that TFF1 rs3761376 may serve as a potential biomarker to predict the risk of nephrolithiasis.

Prognostic comparison between radical prostatectomy and radiotherapy in prostate cancer patients at different stages and ages.

Radical prostatectomy (RP) and radiotherapy (RT) are both evidence-based nonconservative treatments for prostate cancer (PCa). However, which treatment is better remains controversial. This study aimed to compare the prognostic difference between radical prostatectomy (RP) and radiotherapy (RT) in PCa patients at different stages and ages. Two independent PCa cohorts (the Surveillance, Epidemiology, and End Results, SEER; and the Prostate, Lung, Colorectal, and Ovarian, PLCO) were employed. Cox regression was used to calculate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs). In both cohorts, patients who received RT exhibited a worse prognostic outcome than those who underwent RP. When stratified analysis was performed by tumor node metastasis (TNM) stage and age at diagnosis in the SEER cohort, the HR of RT versus RP for overall survival increased with TNM stage but decreased with age. Specifically, PCa patients in stage I in the age range of 55-84 years, stage IIA at 70-85+ years, and stage IIB at 75-85+ years had better survival with RT than RP patients (p < 0.05). In contrast, patients in stages IIA, IIB, III and IV with respective age ranges of 55-64 years; 50-74 years; 55-59, 65-74 years; and 45-74 years showed worse survival with RT compared with RP (p < 0.05). These findings were partially validated in the PLCO dataset. Our results indicated that the choice between RT and RP should be guided by TNM stage and age. These findings may facilitate counseling regarding the prognostic effect of RT and RP for PCa patients.

Circulating let-7f-5p improve risk prediction of prostate cancer in patients with benign prostatic hyperplasia.

Background: Although the prostate-specific antigen (PSA) testing was widely used for early detection of prostate cancer (PCa), it is difficult for PSA to distinguish the PCa from benign prostatic hyperplasia (BPH) patients. Emerging evidence has shown that microRNA (miRNA) was a promising biomarker for PCa screening. Methods: We applied miRNA profiling from microarray or high-throughput sequencing in Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to identify the differentially expressed miRNAs in PCa patients (n = 1,017) and controls (n = 413). Then, qRT-PCR analysis was used to validate the expression of candidate miRNAs in our independent cohort, include 66 PCa cases and 63 BPH patients diagnosed by biopsy. The area under the receiver operating characteristic curve (AUC) was conducted to evaluate the diagnostic efficacy of miRNAs and PSA. Results: In the microarray analysis, we identified two consistently differently expressed miRNAs (miR-103a-3p and let-7f-5p) between PCa patients and controls. In the subsequent qRT-PCR analysis, the let-7f-5p was upregulated in PCa compared with BPH patients (P=2.17E-07), but no statistically difference of miR-103a-3p expression was observed (P=0.456). The AUC was 0.904 for combination of lef-7f-5p and PSA, which was significantly higher than that of let-7f-5p (0.782) or PSA (0.795) alone (P=7.55E-04 and P=2.09E-03, respectively). Besides, the results of decision curve analysis and nomogram prediction indicated that combination of let-7f-5p and PSA had superior predictive accuracy of PCa. Conclusions: Our study suggests that plasma let-7f-5p combining PSA could serve as potentially diagnostic biomarkers for PCa.

LncRNA PCAT1 and its genetic variant rs1902432 are associated with prostate cancer risk.

Emerging evidence has showed that lncRNAs and trait-associated loci in lncRNAs play a crucial role in the progression of cancer including prostate cancer (PCa).This study aimed to investigate the molecular mechanisms of lncRNA PCAT1 involved in PCa development and its genetic variant associated with PCa risk. We applied cell proliferation and apoptosis assays to assess the effect of PCAT1 on PCa cell phenotypes. In addition, the genome-wide profiling of gene expression was assessed from three pairs of DU145 cells transfected with PCAT1 overexpression vector or negative control (NC) vector. Furthermore, a case-control study was conducted to explore the associations of four tagging single nucleotide polymorphisms (tagSNPs) and PCa risk in 850 PCa cases and 860 cancer-free controls. Our results showed that lncRNA PCAT1 promoted cell proliferation and inhibited cell apoptosis. Ingenuity pathway analysis (IPA) indicated that dysregulated mRNAs induced by overexpression of PCAT1 were primarily enriched in androgen-independent prostate tumor term and implicated in the disease and functions networks, such as cell death and survival, cell proliferation and gene expression. Besides, rs1902432 in PCAT1 was significantly associated with increased risk of PCa (Additive model: OR = 1.19, P = 0.014; Co-dominant model: CC vs. TT, OR = 1.45, P =0.012; Recessive model: CC vs. TT/CT, OR= 1.34, P = 0.027). This study suggests that PCAT1 may act as an oncogene through promoting cell proliferation and suppressing cell apoptosis in PCa development, and genetic variant in PCAT1 contributes to the susceptibility to PCa.

Calcium-Sensing Receptor Genetic Polymorphisms and Risk of Developing Nephrolithiasis in a Chinese Population.

OBJECTIVE: To evaluate the association between calcium-sensing receptor (CaSR) Arg990Gly (rs1042636, A > G), Ala986Ser (rs1801725, G > T) polymorphisms, and urolithiasis risk. METHODS: Polymorphisms mentioned above were genotyped in a hospital-based case-control study of 615 patients diagnosed with nephrolithiasis and 315 kidney stone-free controls in a Chinese population using the SNaPshot method. RESULTS: The results indicated a significantly increased risk associated with CaSR Arg990Gly GG genotypes (OR 1.64, 95% CI 1.08-2.50) compared with the AA genotype. The CaSR Arg990Gly G carriers (AG/GG) had an adjusted OR (95% CI) of 1.45 (1.04-2.03, p = 0.021) compared with the wild genotype in the dominant model. In the stratified analyses, the risk remained for the subgroup of patients with age >48, never smokers and patients with hypertension and calcium oxalate stones (OR 1.78, 95% CI 1.02-3.09; OR 1.54, 95% CI 1.03-2.30; OR 2.83, 95% CI 1.32-6.07; OR 1.60, 95% CI 1.12-2.28, respectively). CONCLUSION: Our results provide evidences that the CaSR Arg990Gly polymorphism is associated with the risk of nephrolithiasis development in a Chinese population.

The HOTAIR, PRNCR1 and POLR2E polymorphisms are associated with cancer risk: a meta-analysis.

Long non-coding RNAs (LncRNAs) have been widely studied and aberrant expression of lncRNAs are involved in diverse cancers. Genetic variation in lncRNAs can influence the lncRNAs expression and function. At present, there are many studies to investigate the association between lncRNAs polymorphisms and cancer susceptibility. However, it has no systematic study to evaluate the association. We performed a meta-analysis to summarize the results of common lncRNAs (HOTAIR, PRNCR1, POLR2E and H19) polymorphisms on cancer risk, by using the random-effect model to obtain the odds ratio (ORs) and 95% confidence interval (95%CI). We also applied the meta-regression and publication bias analysis to seek the source of heterogeneity and evaluate the stability of results, respectively. The summary results indicated that HOTAIR rs920778 increased the cancer risk in recessive model (OR = 1.61, 95% CI = 1.08-2.41, Pheterogeneity<0.001). For PRNCR1 (rs1016343, rs16901946) and POLR2E (rs3787016), we also found the significant association with incresed risk of cancer (all P<0.05). However, we did not observe any significant association between H19 rs2107425 and cancer risk. Our meta-analysis results revealed that these four lncRNAs polymorphisms (HOTAIR rs920778, PRNCR1 rs1016343 and rs16901946, POLR2E rs3787016) can contribute to cancer risk. Further studies should confirm these findings.

Association between OPN genetic variations and nephrolithiasis risk.

Osteopontin (OPN) has an important role in urolithiasis. However, few studies have explored the association between OPN genetic variants and urolithiasis risk. In the present study, three single-nucleotide polymorphisms (SNPs) (rs28357094, rs11439060 and rs11730582) located on the promoter of OPN were genotyped in a total of 480 individuals, including 230 nephrolithiasis patients and 250 matched healthy controls, and the associations between these SNPs and nephrolithiasis risk in different genetic models was assessed. No significant differences were identified in the genotype and allele frequencies of OPN rs28357094 or rs11730582 (P=0.805 for rs28357094; P=0.577 for rs11730582, respectively). However, carriers with the OPN rs11439060 insertion (ins) types (ins/deletion and ins/ins) were overrepresented in urolithiasis patients compared with the controls [odds ratio (OR), 1.55; 95% confidence interval (CI), 1.08-2.22]. In the stratified analysis, the increased risk was more evident among younger subjects (adjusted OR, 1.68; 95% CI, 1.01-2.81), females (2.15; 1.14-4.08), overweight subjects (1.80; 1.07-3.05), normotensive subjects (2.48; 1.02-6.00), abnormal blood sugar subjects (1.58; 1.08-2.30), smokers (1.63; 1.02-2.60), and ever-drinkers (1.98; 1.10-3.60).. These findings revealed that the OPN rs11439060 polymorphism may act as genetic biomarker for the detection of high-risk nephrolithiasis patients.

Association Between MIF-AS rs755622 and Nephrolithiasis Risk in a Chinese Population.

BACKGROUND Single-nucleotide polymorphisms (SNPs) located at lncRNA may affect the stability and splicing processes of mRNA formation, which result in the alteration of its interacting partners. The SNP rs755622 within exon of antisense lncRNA MIF- AS and promoter of MIF was implicated in renal disease risk. MATERIAL AND METHODS In this case-control study, we genotyped the SNP rs755622 in 230 patients diagnosed with nephrolithiasis and 250 controls in a Chinese population. RESULTS We found that the rs755622 CG and CC genotypes had a significantly increased nephrolithiasis risk (adjusted OR=1.52, 95% CI=1.03-2.25; OR=2.63, 95% CI=1.21-5.72, P=0.015), compared with GG genotype in the additive model. The rs755622 C carriers (GC/CC) had an adjusted OR (95% CI) of 1.65 (1.14-2.39, P=0.016), compared with the GG genotype in the dominant model. This hazardous effect was more pronounced in subgroup age >46, BMI >24, hypertension, ever smoking, and ever drinking subjects. Moreover, we found that rs755622 could modulate the function of MIF-AS by influencing its folding. CONCLUSIONS These results indicate that the MIF-AS rs755622 polymorphism may have a crucial role in the development of nephrolithiasis.

Macrophage migration inhibitory factor gene -173G>C polymorphism and risk of bladder cancer in southeast China: a case-control analysis.

Inflammatory factors may promote carcinogenesis. Macrophage migration inhibitory factor (MIF), which is derived from T-cell, known as a member of the transforming growth factor-ß (TGF-ß) superfamily, plays an important role in the pro- and anti-inflammatory response to infection and in the etiology of bladder cancer. We hypothesized that MIF-173 locus polymorphism might contribute to genetic susceptibility to bladder cancer. In a hospital-based case-control study of 325 patients with bladder cancer and 345 cancer-free controls frequency-matched by age, sex, smoking status, and alcohol use, we genotyped the MIF polymorphism and analyzed immunohistochemical stained operational bladder cancer tissue sections for MIF. We found that individuals with GC/CC genotype had a significantly decreased risk of bladder cancer (adjusted OR = 0.57, 95% CI, 0.41-0.79) than those with GG genotype. In the stratification analysis, we found that the decreased risk was more pronounced among older subjects (adjusted OR = 0.56, 95% CI, 0.39-0.81), men (0.47, 0.33-0.68), smokers (0.54, 0.35-0.85), and ever-drinkers (0.44, 0.27-0.71). The percentage of positive staining in the cytoplasm and nucleus in the normal and bladder cancer with CC/GC genotype tissues was higher than that of GG genotype bladder cancer tissue(39.1% vs. 75.0% in strong staining for GG and GC/CC genotypes, respectively, P = 0.028). In conclusion, MIF -173G>C polymorphism may play a role in the etiology of bladder cancer in southern Chinese population. Large studies are warranted to validate our findings.