Background Alterations in the RGS pathway have been implicated in several cancers; therefore, we determined their role in overall bladder cancer risk, recurrence, progression and survival. Methods This is a case-control series of 803 bladder cancer patients with a frequency-matched cohort of 803 healthy individuals. We evaluated 95 SNPs in 17 RGS genes for association with overall bladder cancer risk, recurrence and progression in patients with non-muscle invasive bladder cancer (NMIBC), and death in patients with muscle invasive bladder cancer (MIBC). Cumulative effects and Classification and Regression Tree analyses were performed for SNPs associated with overall bladder cancer risk. Kaplan-Meier graphs were created to evaluate survival differences in patients with MIBC. Results Rs10759 on the RGS4 gene demonstrated the highest association with overall bladder cancer risk conferring a 0.77 fold reduced risk with the increasing number of variant alleles (P<0.001). Cumulative effects analysis, including all five significant SNPs, demonstrated increasing risk with the number of unfavorable genotypes (OR 4.13, 95% CI 2.14–7.98). Eleven and thirteen SNPs were identified to be associated with recurrence and progression in NMIBC, respectively. Of the 10 SNPs associated with death in MIBC, rs2344673 in an additive model was the most significant and associated with a decreased median survival of 13.3 months compared to 81.9 months in individuals without a variant allele. Conclusion Genetic variations in the RGS pathway are associated with overall risk of bladder cancer, recurrence and progression in patients with NMIBC, and risk of death in patients with MIBC.
Inflammation plays a critical role in the etiology of several cancers and may affect their clinical outcome. Our objective was to assess the association of genetic variants within the inflammation pathway with recurrence and progression among non-muscle invasive bladder cancer (NMIBC) patients with or without Bacillus Calmette–Guérin (BCG) treatment. We genotyped 372 single nucleotide polymorphisms (SNPs) in 27 selected genes within the inflammation pathway in 349 patients diagnosed with NMIBC, followed by internal validation in 322 additional patients. We used Cox proportional hazards regression analyses to identify SNPs as predictors for recurrence and progression. In the discovery phase, we identified 20 variants that were significantly associated with recurrence outcomes and 15 SNPs significantly associated with progression in patients treated with BCG but not in the transurethral resection (TUR)-only group. In BCG treated patients, rs7089861 was the only SNP significantly associated with risk of progression in both the discovery phase (Hazard Ratio [HR]=3.15, 95% Confidence Interval [CI]: 1.38-7.22, P<0.01) and validation phase (HR=3.84, 95% CI: 1.64-9.0, P=0.002; meta-analysis HR=3.47, 95% CI: 1.92-6.28, P<0.001). Two variants, rs1800686 and rs2071081, had probable association with HRs of the same trend in the discovery and validation groups (meta-analysis P=0.002). These findings supported the notion that genetic variation of inflammation pathway may impact clinical outcome of NMIBC patients treated with BCG immunotherapy. Further validation of these results in order to improve risk stratification to identify patients most likely to benefit from BCG treatment versus upfront radical cystectomy and future development of potential targeted therapies are warranted.Significance StatementIn a two-stage study, we identified several genetic variants in the inflammation pathway associated with recurrence and progression in early-stage bladder cancer. In particular, variant rs7089861 was validated for progression among patients who underwent BCG immunotherapy. Several other variants showed marginal association with recurrence or progression. These findings suggest that inflammatory pathway genetic variants may influence clinical outcome of bladder cancer patients and help to select patients most appropriate for BCG treatment.
Background: Colorectal cancer (CRC) is one of the most prevalent and deadly cancers in the world. The development of improved and robust biomarkers to enable screening, surveillance, and early detection of CRC continues to be a challenge. Patients with colorectal adenoma are at higher risk of developing colon cancer; however, noninvasive methods to identify these patients are still on demand. The aim of this study was to identify biomarkers of CRC disease progression by using metabolomic profiling of human serum samples in a multistep approach. Methods: We performed global metabolomic profiling on 30 human serum samples from patients with colorectal adenoma, 30 CRC patients and 30 healthy controls who were matched by age, gender and ethnicity. For validation, we measured the three top differentially expressed metabolites in an additional set of 50 adenoma, 50 CRC and 50 healthy controls. Results: Global biochemical profiles of 404 metabolites were detected, with 301 metabolites remaining after quality control procedures. In discovery phase, 50 metabolites had differential levels between colorectal adenoma, CRC and controls (P for trend <0.05), with 19 metabolites showing increased levels in CRC and adenoma in comparison to controls and 31 metabolites with decreased levels. Further exploratory analyses of these metabolites showed a key role for metabolic pathways involving urea cycle, caffeine and galactose metabolism as associated with CRC progression. The top 3 differentially expressed metabolites (Xanthine, Hypoxanthine and D-mannose) were selected for validation. Consistent with the discovery phase, CRC cases and adenoma had lower levels of Xanthine than controls (mean ± SD; 9.95 ±0.92 mg/ml vs 10.63±0.97 mg/ml; P<0.001 and 9.87±0.75 vs 10.63±0.97 mg/ml; P<0.001). The same trend was observed for Hypoxanthine (mean ± SD; 10.72 ±0.62 mg/ml vs 12.29±1.60; P<0.001 and 10.71±0.61 vs 12.29±1.60 mg/ml; P <0.001) whereas higher levels of D-mannose where observed in both CRC cases and adenoma when compared to controls (3.32±0.58 mg/ml vs 2.32 ±0.90mg/ml; P<0.001 and 3.32±0.58 mg/ml vs 2.32 ±0.90mg/ml; P<0.001). Using the median value of controls as a cut-off point, 94% of the adenoma and CRC cases showed low levels of Xanthine (Odds Ratio (OR) = 10.47, 95% confidence interval (CI) = 2.63-41.63 for adenoma; OR = 38.76 and 95% CI = 6.58-228.51 for CRC). For Hypoxanthine, 90% of the adenoma and CRC cases showed low levels (OR = 6.50 and 95% CI = 1.98–21.24 for adenoma; OR = 11.19 and 95% CI = 3.28-38.21 for CRC). For D-Mannose, all adenoma cases had high levels (OR is not available due to 0 count) and 92% of CRC cases (OR = 15.99, 95% Ci = 4.07-62.88, P< 0.001) had high levels of D-Mannose, compared to 50% of controls having high levels of D-Mannose. Conclusions: Our results suggest the potential utility of the identified metabolites as new valuable biomarkers for early detection of CRC. Citation Format: Beatriz Sanchez-Espiridion, Lindsey White, Lopa Mishra, Gottumukkala S. Raju, Scott Kopetz, Jian Gu, Yuanquing Ye, Xifeng Wu, Dong Liang. Global and targeted metabolomic profiling of colorectal cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 8.
As an essential nutrient that facilitates DNA synthesis, cell proliferation and metabolism, iron is involved in carcinogenesis. While epidemiological studies suggest a J-shaped model for the relationship of serum iron level and cancer risk with both too low and too high levels associated with increased cancer risks, the effect of genetic variants related to intracellular iron regulatory pathway and dietary iron intake on non-small cell lung cancer (NSCLC) risk is little known. In this study, we evaluated a panel of miRNA related genetic variants in iron regulatory pathway genes on the risk of NSCLC. In discovery phrase, 157 miRNA related single nucleotide polymorphisms (SNPs) from 81 genes of iron regulatory pathway were genotyped in 1656 NSCLC cases and 1486 healthy controls. Eight SNPs in 6 genes were significantly associated with risk of NSCLC. A SNP in 3’ UTR of Iron-Responsive Element Binding Protein 2 (IREB2) gene at 15q25 region was subsequently replicated in dbGaP lung cancer GWAS dataset. Combining all subjects (7,352 cases, 7,296 controls), the overall P-value was 4.9 × 10−9 (Odds ratio (OR) = 0.86). eQTL analysis showed that the SNP on IREB2 alters IREB2 gene expression (P = 3.0 × 10−11). The SNP is predicted to alter a miR-29 binding site on IREB2 gene and indeed the expression of miR-29 is inversely correlated with IREB2 expression in tumor tissues. We then determined the expression of serum miR-29a in 150 early-stage NSCLC patients and 172 healthy controls and found that miR-29a was significantly associated with higher risk of cancer (OR = 1.78, P = 0.03). By analyzing dietary intake information of the discovery population, iron intake was significantly associated with risk of NSCLC in logistic regression analysis and there was also evidence of a synergistic interaction with between the SNP and iron intake in modulating NSCLC risk (P for interaction = 0.01). Taken together, SNPs at miRNA binding sites of iron regulatory pathway genes and dietary iron intake may modify risk of NSCLC individually and jointly. Citation Format: Liren Zhang, Yuanquing Ye, Huakang Tu, Michelle A.t. Hildebrandt, John V. Heymach, Jack A. Roth, Jian Gu, Xifeng Wu. Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 809.
Introduction: Colorectal cancer (CRC) continues to rank as one of the most common cancers in the U.S. and around the world. Colorectal adenoma is the well-established precursor of CRC, yet only a very small proportion of adenomas progress to CRC. Therefore, identification of biomarker associated with adenoma progression is vital for risk stratification and development of intervention strategies. We hypothesize that genomic analysis of adenoma will lead to better understanding of tumorigenesis and identification of novel biomarkers. Methods: We carried out whole exome sequencing (WES) on tissues and paired blood in 14 sessile serrated adenoma (SSA) and 36 tubulovillous adenoma (TVA) patients. Frequently mutated genes from TVA along with significantly mutated genes of TCGA colorectal adenocarcinoma were further investigated in an additional 100 pairs of TVA by targeted sequencing. Results: 1) WES revealed similar somatic mutation frequency but distinctive mutated genes in TVA and SSA. 2) All adenomas included in WES were non-hypermutators with mutation frequency ranged from 0.55 to 3.71 (average: 1.49) non-silent somatic mutations per million base, which is significantly lower than that of TCGA non-hypermutators that ranged from 0.48 to 10.11 (average 4.47, p < 2.2×10⁁-16). 3) MutSigCV v1.4 discovered shared and unique significantly-mutated genes (SMG) in TVA and SSA reflecting difference in biology. 4) Targeted sequencing confirmed the findings in WES with a better estimate of population frequency for genes of interest. 5) Unsupervised clustering achieved high discrimination between adenoma and adenocarcinoma. 6) A subset of mutations that best discriminate adenoma and adenocarcinoma were identified by random Forest. Conclusions: We discovered a set of genes with distinctive mutation pattern between adenoma and adenocarcinoma. We are conducting functional analysis to explore the potential of these genes as progression driver and risk predictors. We predict that the findings of this project will help lay the foundation to inform development of surveillance program and preventive intervention in CRC. Citation Format: Shu-Hong Lin, Gottumukkala S. Raju, Chad Huff, Jian Gu, Jiun-Shen Chen, Scott Kopetz, David G. Menter, Ernest Hawk, Lopa Mishra, Yuanquing Ye, Xifeng Wu. Mutational landscape of colorectal adenomas reveals potential signatures for progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 143.
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