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author:("Lin, moulin")
1.  PPP1R12A Copy Number Is Associated with Clinical Outcomes of Stage III CRC Receiving Oxaliplatin-Based Chemotherapy 
Mediators of Inflammation  2015;2015:417184.
Aim. To investigate the correlation between PPP1R12A gene copy number and clinical outcomes of oxaliplatin-based regimen in stage III colorectal cancer (CRC). Methods. A total of 139 paraffin-embedded tissue samples of stage III CRC patients who received oxaliplatin-based treatment after radical surgery were recruited. Genomic DNA was extracted and purified from paraffin-embedded sections. Quantitative PCR methods were used to detect the relative copy number (RCN) of PPP1R12A. Results. Statistical analysis demonstrated that low PPP1R12A RCN was associated with poor RFS (HR = 2.186, 95% CI: 1.293–3.696; P = 0.003) and OS (HR = 2.782, 95% CI: 1.531–5.052; P < 0.001). Additionally, when patients were stratified according to subgroups of stage III and tumor location, poor RFS and OS were also observed in the low PPP1R12A RCN group with significance (RFS: IIIB HR = 2.870, P < 0.001; colon HR = 1.910, P = 0.037; OS: IIIB HR = 3.527, P < 0.001; IIIC HR = 2.662, P = 0.049; rectum HR = 4.229, P = 0.002). Conclusion. Our findings suggest the copy number of PPP1R12A can independently predict recurrence and overall survival of stage III colorectal cancer patients receiving oxaliplatin-based chemotherapy.
PMCID: PMC4465766  PMID: 26113782
2.  PIK3C2G copy number is associated with clinical outcomes of colorectal cancer patients treated with oxaliplatin 
Purpose: To investigate whether the copy number of PIK3C2G is associated with clinical outcomes for stage III colorectal cancer (CRC) patients treated with oxaliplatin-based chemotherapy. Methods: A total of 142 CRC patients who received first-line oxaliplatin-based chemotherapy after curative surgery in Ruijin Hospital and The Tenth People’s Hospital were recruited in this study. Patients were enrolled between June 2006 and December 2011, with follow-up to January 2014. Quantitative real-time PCR method was used to detect the copy number of PIK3C2G. Cox proportional hazards model and Kaplan-Meier curves were used to analyze the association between PIK3C2G copy number and clinical outcome. Results: In patients with stage III disease, low copy number of PIK3C2G was associated with increased risk of both recurrence (HR, 2.44, 95% CI, 1.33-4.47, P=0.004) and death (HR, 2.89, 95% CI, 1.49-5.60, P=0.002). Multivariate analysis also indicated that low PIK3C2G copy number was a significant and independent predictor of OS and RFS of stage III CRC. Conclusions: PIK3C2G is capable of predicting the recurrence and overall survival of stage III CRC patients receiving oxaliplatin-based therapy.
PMCID: PMC4358559  PMID: 25785104
PIK3C2G; recurrence; overall survival; colorectal cancer; oxaliplatin
3.  Genetic polymorphisms in microRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients 
To evaluate the effects of single-nucleotide polymorphisms (SNPs) in microRNA-related genes on clinical outcomes in colorectal cancer (CRC) patients receiving first-line fluoropyrimidine-based chemotherapy.
Experimental Design
Forty-one SNPs in 26 microRNA-related genes were genotyped in 1,097 CRC patients recruited at the University of Texas MD Anderson Cancer Center. Patients were enrolled between 1990 and 2008 and last follow-up was in 2010. The associations between genotypes and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) stratified by clinical stage were analyzed in 741 newly diagnosed patients (diagnosed within 1 year) and replicated the findings in additional 356 patients.
In patients with stage III disease, mir608:rs4919510 was associated with increased risk for both recurrence (HR=2.72; 95%CI, 1.38 to 5.33) and death (HR=3.53; 95%CI, 1.42 to 8.73). The associations were confirmed in the replication set and the combined HR for training and replication sets was 1.94 (95% CI, 1.31 to 2.86) for recurrence and 2.35 (95%CI, 1.40 to 3.93) for death, respectively. The mir219-1:rs213210 showed consistent association with death in the training set (HR=3.86; 95%CI, 1.33 to11.22), the replication set (HR = 3.33; 95% CI, 1.39 to 7.98) and combined dataset (HR = 3.53; 95% CI, 1.80 to 6.95). In combined analysis of these two SNPs, patients carrying the variant genotypes at both sites exhibited a 5.6 fold increased risk of death.
Genetic polymorphisms in the microRNA pathway may predict prognosis in stage III CRC patients treated with fluoropyrimidine-based chemotherapy.
PMCID: PMC4141857  PMID: 22661538
colorectal cancer; polymorphism; microRNA; chemotherapy; recurrence; survival
4.  Identification of polymorphisms in ultraconserved elements associated with clinical outcomes in locally advanced colorectal adenocarcinoma 
Cancer  2012;118(24):6188-6198.
Ultraconserved elements (UCEs) are non-coding genomic sequences completely identical among human, mouse, and rat species and harbor critical biological functions. We hypothesized that single nucleotide polymorphisms (SNPs) within UCEs are associated with clinical outcomes in colorectal cancer (CRC) patients.
Patients and Methods
Forty-eight SNPs within UCEs were genotyped in 662 patients with stage I–III CRC. The associations between genotypes and recurrence and survival were analyzed in stage II or III patients receiving fluoropyrimidine-based adjuvant chemotherapy using a training and validation design. The training set contained 115 stage II and 170 stage III patients, and the validation set contained 88 stage II and 112 stage III patients, respectively.
Eight SNPs were associated with clinical outcomes stratified by disease stage. In particular, for stage II patients with at least one variant allele of rs7849, consistent association with increased recurrence risk was observed in the training set (HR: 2.39; 95%CI: 1.04–5.52), replication set (HR: 3.70; 95%CI: 1.42–9.64), and meta-analysis (HR: 2.89; 95%CI: 1.54–5.41). There were several other SNPs that were significant in training set, but not in the validation set. These include: rs2421099, rs16983007 and rs10211390 with recurrence, and rs6590611 with survival in stage II patients; and SNPs rs6124509 and rs11195893 with recurrence in stage III patients. In addition, we also observed significant cumulative effect of multiple risk genotypes and potential gene-gene interactions on recurrence risk.
This is the first study to evaluate the association between SNPs within UCEs and clinical outcome in CRC patients. Our results suggest that SNPs within UCEs may be valuable prognostic biomarkers for locally advanced CRC patients receiving 5FU-based chemotherapy.
PMCID: PMC3465518  PMID: 22673945
SNP; ultraconserved elements; colorectal cancer; recurrence
5.  Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma 
Carcinogenesis  2012;33(4):841-847.
We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63–1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52–0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02–3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02–4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene–gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.
PMCID: PMC3324446  PMID: 22318908
6.  Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer 
Carcinogenesis  2011;32(7):1050-1056.
The magnitude of benefit is variable for advanced non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy. The purpose of this study is to determine whether genetic variations in the transforming growth factor-beta (TGF-β) pathway are associated with clinical outcomes in NSCLC patients receiving first-line platinum-based chemotherapy. Five hundred and ninety-eight advanced-stage NSCLC patients who received first-line platinum-based chemotherapy with or without radiotherapy were recruited at the MD Anderson Cancer Center between 1995 and 2007. DNA from blood was genotyped for 227 single nucleotide polymorphisms (SNPs) in 23 TGF-β pathway-related genes to evaluate their associations with overall survival. In individual SNP analysis, 22 variants were significantly associated with overall survival, of which the strongest associations were found for BMP2:rs235756 [hazard ratio (HR) = 1.45; 95% confidence interval (CI), 1.11–1.90] and SMAD3:rs4776342 (HR = 1.25; 95% CI, 1.06–1.47). Fifteen and 18 genetic loci displayed treatment-specific associations for chemotherapy and chemoradiation, respectively, identifying a majority of the cases who would be predicted to respond favorably to a specific treatment regimen. BMP2:rs235753 and a haplotype in SMAD3 were associated with overall survival for both treatment modalities. Cumulative effect analysis showed that multiple risk genotypes had a significant dose-dependent effect on overall survival (Ptrend = 2.44 x 10−15). Survival tree analysis identified subgroups of patients with dramatically different median survival times of 45.39 versus 13.55 months and 18.02 versus 5.89 months for high- and low- risk populations when treated with chemoradiation and chemotherapy, respectively. These results suggest that genetic variations in the TGF-β pathway are potential predictors of overall survival in NSCLC patients treated with platinum-based chemotherapy with or without radiation.
PMCID: PMC3128559  PMID: 21515830

Results 1-6 (6)