Xiaoxiang Guan

The VEGF -634G>C promoter polymorphism is associated with risk of gastric cancer

BackgroundBoth TGF-β1 and VEGF play a critic role in the multiple-step process of tumorgenesis of gastric cancer. Single nucleotide polymorphisms (SNPs) of the TGFB1 and VEGF genes have been associated with risk and progression of many cancers. In this study, we investigated the association between potentially functional SNPs of these two genes and risk of gastric cancer in a US population.MethodsThe risk associated with genotypes and haplotypes of four TGFB1 SNPs and four VEGF SNPs were determined by multivariate logistic regression analysis in 171 patients with gastric cancer and 353 cancer-free controls frequency-matched by age, sex and ethnicity.ResultsCompared with the VEGF-634GG genotype, the -634CG genotype and the combined -634CG+CC genotypes were associated with a significantly elevated risk of gastric cancer (adjusted OR = 1.88, 95% CI = 1.24-2.86 and adjusted OR = 1.56, 95% CI = 1.07-2.27, respectively). However, none of other TGFB1 and VEGF SNPs was associated with risk of gastric cancer.ConclusionOur data suggested that the VEGF-634G>C SNP may be a marker for susceptibility to gastric cancer, and this finding needs to be validated in larger studies.

Incorporating Single-nucleotide Polymorphisms Into the Lyman Model to Improve Prediction of Radiation Pneumonitis

PURPOSE To determine whether single-nucleotide polymorphisms (SNPs) in genes associated with DNA repair, cell cycle, transforming growth factor-β, tumor necrosis factor and receptor, folic acid metabolism, and angiogenesis can significantly improve the fit of the Lyman-Kutcher-Burman (LKB) normal-tissue complication probability (NTCP) model of radiation pneumonitis (RP) risk among patients with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS Sixteen SNPs from 10 different genes (XRCC1, XRCC3, APEX1, MDM2, TGFβ, TNFα, TNFR, MTHFR, MTRR, and VEGF) were genotyped in 141 NSCLC patients treated with definitive radiation therapy, with or without chemotherapy. The LKB model was used to estimate the risk of severe (grade≥3) RP as a function of mean lung dose (MLD), with SNPs and patient smoking status incorporated into the model as dose-modifying factors. Multivariate analyses were performed by adding significant factors to the MLD model in a forward stepwise procedure, with significance assessed using the likelihood-ratio test. Bootstrap analyses were used to assess the reproducibility of results under variations in the data. RESULTS Five SNPs were selected for inclusion in the multivariate NTCP model based on MLD alone. SNPs associated with an increased risk of severe RP were in genes for TGFβ, VEGF, TNFα, XRCC1 and APEX1. With smoking status included in the multivariate model, the SNPs significantly associated with increased risk of RP were in genes for TGFβ, VEGF, and XRCC3. Bootstrap analyses selected a median of 4 SNPs per model fit, with the 6 genes listed above selected most often. CONCLUSIONS This study provides evidence that SNPs can significantly improve the predictive ability of the Lyman MLD model. With a small number of SNPs, it was possible to distinguish cohorts with >50% risk vs <10% risk of RP when they were exposed to high MLDs.

p27Kip1 as a prognostic factor in breast cancer: a systematic review and meta-analysis

The aim of this study was to comprehensively evaluate via a meta‐analysis the association between p27 expression and clinical outcome in breast cancer patients. We conducted a meta‐analysis of 20 studies (n= 6463 patients) that evaluated the correlation between p27 expression and indicators of breast cancer clinical outcome, including overall survival (OS), disease‐free survival (DFS) and relapse‐free survival (RFS). Data pooling was performed by RevMan 4.2. A total of 60% (9 of 15) of the studies showed a significant association between p27 high expression and OS, whereas 25% (2 of 8) and 60% (3 of 5) studies demonstrated a correlation between p27 high expression and DFS and RFS, respectively. The relative risks (RRs) were 1.34 (1.26–1.42) for OS (P < 0.00001), 1.27 (1.10–1.47) for DFS (P= 0.001) and 1.49 (0.92–2.42) for RFS (P= 0.10). In lymph node‐negative breast cancer patients, the RRs for OS and RFS were 1.84 (1.30–2.59; P= 0.0005) and 1.30 (0.20–8.50; P= 0.78), respectively. In lymph node‐positive breast cancer patients, the RRs for OS and RFS were 2.99 (1.77–5.07; P < 0.0001) and 1.49 (0.80–2.77; P= 0.21), respectively. This meta‐analysis indicates that reduced p27 is an independent prognostic factor for poor overall and disease‐free cancer survival.

Association of TGF-β1 Genetic Variants with HPV16-positive Oropharyngeal Cancer

Purpose: Transforming growth factor-β1 (TGF-β1) plays an important role in inflammation and immune responses, which control the human papillomavirus (HPV) clearance and escape of immune surveillance, and may contribute to genetic susceptibility to HPV16 infection. Experimental Design: In this case series study, we analyzed the HPV16 status in tumor specimens and genotyped three TGF-β1 polymorphisms using genomic DNA from the blood of 200 squamous cell carcinoma of the oropharynx (SCCOP) cases. We calculated odds ratio (OR) and 95% confidence intervals (95% CI) in univariate and multivariable logistic regression models to examine the association between the TGF-β1 polymorphisms and HPV16 status in SCCOP. Results: Compared with those with the common homozygous genotype, the TGF-β1 T869C variant genotypes were significantly associated with HPV16-positive tumor status among patients with SCCOP (OR, 1.97; 95% CI, 1.03-3.76), but no significant association was observed for the TGF-β1 C509T or G915C polymorphism. When all variant genotypes were combined, however, SCCOP patients carrying genotypes with any of these TGF-β1 variants were more than twice as likely to have an HPV16-positive tumor (OR, 2.28; 95% CI, 1.16-4.50) as patients with no variant genotypes. The stratified analysis showed that those under 54 years of age, non-Hispanic white patients, never smokers, and never drinkers with any variant TGF-β1 genotypes were also more likely to have HPV16-positive tumors. Conclusions: TGF-β1 polymorphisms may serve as a susceptibility marker for tumor HPV16 status among SCCOP patients, particularly those who were never smokers and never drinkers. Large studies are needed to validate our findings. Clin Cancer Res; 16(5); 1416–22

A functional variant at the miR-885-5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer

Caspases are important regulators and executioners in the apoptosis pathways and play crucial roles in carcinogenesis. We tested the hypothesis that functional variants of CASP genes are associated with risk of squamous cell carcinoma of the head and neck (SCCHN) and second primary malignancy (SPM). We genotyped 7 selected, potentially functional single nucleotide polymorphisms (SNPs) located in the microRNA binding sites of the 3′ untranslational region (UTR; 2 in CASP3, 1 in CASP6, and 4 in CASP7) and evaluated their associations first with risk of SCCHN in 1066 patients with SCCHN and 1074 cancer‐free control subjects and then with SPM in 846 patients in the same non‐Hispanic white study population. We found that compared with the CASP3 TT genotype of rs1049253, the variant TC/CC genotypes were associated with significantly increased risk of SCCHN (adjusted odds ratio = 1.29 and 95% confidence interval 1.07‐1.56) and SPM (adjusted hazard ratio = 1.79 and 95% CI=1.02–3.16) and worse SPM‐free survival (log‐rank P = 0.020), but no associations were found for the other 6 SNPs. We then performed additional experiments to seek functional relevance of the rs1049253 SNP. First, the luciferase activity and miR‐885‐5p mimic transfection tests suggested that CASP3 was the target of miR‐885‐5p and that rs1049253T>C resulted in altered regulation of the CASP3 expression. Second, the rs1049253 CC genotype was associated with reduced levels of CASP3 mRNA in peripheral blood mononuclear cells from 118 SCCHN patients and 103 cancer‐free control subjects and lower levels of CASP3 protein expression in 11 head and neck cancer cell lines, compared with the TT genotype. Taken together, our data suggest that the miR‐885‐5p binding site rs1049253T>C SNP in the 3′‐UTR of CASP3 modulates CASP3 expression at both mRNA and protein levels and thus contributes to SCCHN susceptibility.—Guan, X., Liu, Z., Liu, H., Yu, H., Wang, L.‐E., Sturgis, E. M., Li, G., and Wei, Q. A functional variant at the miR‐885‐5p binding site of CASP3 confers risk of both index and second primary malignancies in patients with head and neck cancer. FASEB J. 27, 1404–1412 (2013). www.fasebj.org

Genotypes and haplotypes of the VEGF gene and survival in locally advanced non-small cell lung cancer patients treated with chemoradiotherapy.

BackgroundVascular endothelial growth factor (VEGF) is a major mediator of angiogenesis involving in carcinogenesis, including lung cancer. We hypothesized that VEGF polymorphisms may affect survival outcomes among locally advanced non-small cell lung cancer (LA-NSCLC) patients.MethodsWe genotyped three potentially functional VEGF variants [-460 T > C (rs833061), -634 G > C (rs2010963), and +936 C > T (rs3025039)] and estimated haplotypes in 124 Caucasian patients with LA-NSCLC treated with definitive radiotherapy. We used Kaplan-Meier log-rank tests, and Cox proportional hazard models to evaluate the association between VEGF variants and overall survival (OS).ResultsGender, Karnofskys performance scores (KPS) and clinical stage seemed to influence the OS. The variant C genotypes were independently associated with significantly improved OS (CT+CC vs. TT: adjusted hazard ratio [HR] = 0.58; 95% confidence interval [CI] = 0.37-0.92, P = 0.022), compared with the VEGF -460 TT genotype.ConclusionsOur study suggests that VEGF -460 C genotypes may be associated with a better survival of LA-NSCLC patients after chemoradiotherapy. Large studies are needed to confirm our findings.

Maintenance Therapy With Immunomodulatory Drugs in Multiple Myeloma: A Meta-Analysis and Systematic Review

BACKGROUND Immunomodulatory drugs (IMiDs) and proteasome inhibitors have dramatically changed management of multiple myeloma (MM). While MM remains incurable, consolidation and maintenance therapy aimed at improving duration of response can potentially improve survival outcomes. A majority of randomized controlled trials (RCTs) have demonstrated benefit of IMiD-based maintenance therapy in delaying disease progression; however, whether this therapy can lead to improved survival remains controversial. METHODS PubMed and abstract databases of major hematology and/or oncology meetings were searched for RCTs that studied maintenance therapy with IMiDs in MM. A meta-analysis was conducted to systematically evaluate the impact of IMiD-based maintenance therapy on survival outcomes and serious adverse events associated with the therapy. All statistical tests were two-sided. RESULTS Eighteen phase 3 RCTs enrolling 7730 patients were included. IMiD-based maintenance therapy statistically significantly prolonged progression-free survival (PFS; hazard ratio (HR) = 0.62, 95% confidence interval (CI) = 0.57 to 0.67, P < .001) but failed to improve overall survival (OS; HR = 0.93, 95% CI = 0.85 to 1.01, P = .082). Stratified analyses demonstrated that both thalidomide and lenalidomide provided PFS but not OS benefit in transplantation as well as nontransplantation settings. IMiD-based maintenance therapy in MM led to a higher risk of grade 3-4 thromboembolism (risk ratio = 2.52, 95% CI = 1.41 to 4.52, P = .002). Thalidomide maintenance therapy increased the risk of peripheral neuropathy; lenalidomide maintenance therapy increased the risks of myelosuppression and second primary hematological malignancies. CONCLUSIONS Thalidomide- or lenalidomide-based maintenance therapy improves PFS but not OS in MM and increases risks of grade 3-4 adverse events, including thromboembolism, peripheral neuropathy, neutropenia, and infection.

Polymorphisms of TGFB1 and VEGF genes and survival of patients with gastric cancer

BackgroundSome TGFB1 and VEGF polymorphisms are believed to be functional. Given that these genes are involved in tumor growth and progression including angiogenesis, dissemination, and invasiveness, we hypothesized that these polymorphisms would be associated with survival in patients with gastric cancer.MethodsWe genotyped TGFB1 -509 C>T, +1869 T>C, and +915 G>C and VEGF -1498T>C, -634G>C, and +936C>T in 167 patients with gastric cancer. Using the Kaplan and Meier method, log-rank tests, and Cox proportional hazard models, we evaluated associations among TGFB1 and VEGF variants with overall, 1-year, and 2-year survival rates.ResultsAlthough there were no significant differences in overall survival rates among all polymorphisms tested, patients with TGFB1+915CG and CC genotypes had a poorer 2-year survival (adjusted hazard ratio (HR), 3.06; 95% confidence interval (CI), 1.09–8.62; P = 0.034) than patients with the GG genotype had. In addition, patients heterozygous for VEGF -634CG also had a poorer 1-year survival (adjusted HR, 2.08; 95% CI, 1.03–4.22; P = 0.042) than patients with the -634GG genotype.ConclusionOur study suggested that TGFB1+915CG/CC and VEGF -634CG genotypes may be associated with short-term survival in gastric cancer patients. However, larger studies are needed to verify these findings.

Polymorphisms of the vascular endothelial growth factor gene and severe radiation pneumonitis in non-small cell lung cancer patients treated with definitive radiotherapy

Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and lung cancer progression. We hypothesized that VEGF polymorphisms may modulate the risk of radiation pneumonitis (RP) in non‐small cell lung cancer (NSCLC) patients treated with definitive radiotherapy. We genotyped three potentially functional VEGF single nucleotide polymorphisms (&460 T > C [rs833061], &634 G > C [rs2010963] and +936 C > T [rs3025039]) and estimated the associations of their genotypes and haplotypes with severe radiation pneumonitis (RP ≥grade 3) in 195 NSCLC patients. We found that the VEGF genotypes of rs2010963 and rs3025039 single nucleotide polymorphisms as well as the &460C/&634G/+936C haplotype were predictors of RP development (adjusted hazard ratio [adjHR] = 2.33, 95% confidence interval [CI], 1.01–5.37, P = 0.047 for CC vs GG genotypes; adjHR = 28.13, 95% CI, 5.24–151.02, P < 0.001 for TT vs CC genotypes; and adjHR = 2.51, 95% CI, 1.27–4.98, P = 0.008 for T‐C‐T vs C‐G‐C haplotypes). In addition, there was a trend towards reduced RP risk in patients carrying an increased number of protective VEGF genotypes. Our data suggest that VEGF polymorphisms can modulate the risk of radiation pneumonitis in NSCLC patients treated with definitive radiotherapy. Large and independent studies are needed to confirm our findings. (Cancer Sci 2012; 103: 945–950)

TNFRSF1B +676 T>G polymorphism predicts survival of non-Small cell lung cancer patients treated with chemoradiotherapy

BackgroundThe dysregulation of gene expression in the TNF-TNFR superfamily has been involved in various human cancers including non-small cell lung cancer (NSCLC). Furthermore, functional polymorphisms in TNF-α and TNFRSF1B genes that alter gene expression are likely to be associated with risk and clinical outcomes of cancers. However, few reported studies have investigated the association between potentially functional SNPs in both TNF-α and TNFRSF1B and prognosis of NSCLC patients treated with chemoradiotherapy.MethodsWe genotyped five potentially functional polymorphisms of TNF-α and TNFRSF1B genes [TNF-α -308 G>A (rs1800629) and -1031 T>C (rs1799964); TNFRSF1B +676 T>G (rs1061622), -1709A>T(rs652625) and +1663A>G (rs1061624)] in 225 NSCLC patients treated with chemoradiotherapy or radiotherapy alone. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard models were used to evaluate associations between these variants and NSCLC overall survival (OS).ResultsWe found that the TNFRSF1B +676 GG genotype was associated with a significantly better OS of NSCLC (GG vs. TT: adjusted HR = 0.38, 95% CI = 0.15-0.94; GG vs. GT/TT: adjusted HR = 0.35, 95% CI = 0.14-0.88). Further stepwise multivariate Cox regression analysis showed that the TNFRSF1B +676 GG was an independent prognosis predictor in this NSCLC cohort (GG vs. GT/TT: HR = 0.35, 95% CI = 0.14-0.85), in the presence of node status (N2-3vs. N0-1: HR = 1.60, 95% CI = 1.09-2.35) and tumor stage (T3-4vs. T0-2: HR = 1.48, 95% CI = 1.08-2.03).ConclusionsAlthough the exact biological function for this SNP remains to be explored, our findings suggest a possible role of TNFRSF1B +676 T>G (rs1061622) in the prognosis of NSCLC. Further large and functional studies are needed to confirm our findings.