Zhensheng Liu

Shortened Telomere length is associated with increased risk of cancer: A meta-analysis

Background Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting. Methods A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ2-based Q statistic test and Eggers test, respectively. Results The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14–1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38–2.44), lung cancer (OR = 2.39, 95% CI = 1.18–4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83–2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53–1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12–2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Eggers test suggested that there was no publication bias in the current meta-analysis (P = 0.532). Conclusions The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.

Genetic variants in selected pre-microRNA genes and the risk of squamous cell carcinoma of the head and neck.

Single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) may alter the processing, transcription, and expression of miRNAs and, thus, may contribute to cancer development. The authors hypothesized that common polymorphisms in pre‐miRNAs are associated individually and (more likely) collectively with the risk of squamous cell carcinoma of the head and neck (SCCHN).

Single Nucleotide Polymorphism at rs1982073:T869C of the TGFβ1 Gene Is Associated With the Risk of Radiation Pneumonitis in Patients With Non–Small-Cell Lung Cancer Treated With Definitive Radiotherapy

PURPOSE In search of reliable biologic markers to predict the risk of normal tissue damage by radio(chemo)therapy before treatment, we investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor 1 (TGFbeta1) gene and risk of radiation pneumonitis (RP) in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Using 164 available genomic DNA samples from patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped three SNPs of the TGFbeta1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by polymerase chain reaction restriction fragment length polymorphism method. We used Kaplan-Meier cumulative probability to assess the risk of grade > or = 3 RP and Cox proportional hazards analyses to evaluate the effect of TGFbeta1 genotypes on such risk. RESULTS There were 90 men and 74 women in the study, with median age of 63 years. Radiation doses ranging from 60 to 70 Gy (median = 63 Gy) in 30 to 58 fractions were given to 158 patients (96.3%) and platinum-based chemotherapy to 147 (89.6%). Grade > or = 2 and grade > or = 3 RP were observed in 74 (45.1%) and 36 patients (22.0%), respectively. Multivariate analysis found CT/CC genotypes of TGFbeta1 rs1982073:T869C to be associated with a statistically significantly lower risk of RP grades > or = 2 (hazard ratio [HR] = 0.489; 95% CI, 0.227 to 0.861; P = .013) and grades > or = 3 (HR = 0.390; 95% CI, 0.197 to .774; P = 0.007), respectively, compared with the TT genotype, after adjustment for Karnofsky performance status, smoking status, pulmonary function, and dosimetric parameters. CONCLUSION Our results showed that CT/CC genotypes of TGFbeta1 rs1982073:T869C gene were associated with lower risk of RP in patients with NSCLC treated with definitive radio(chemo)therapy and thus may serve as a reliable predictor of RP.

Polymorphisms in the DNA Repair Genes XPC, XPD, and XPG and Risk of Cutaneous Melanoma: a Case-Control Analysis

Sunlight causes DNA damage, including bulky lesions that are removed effectively by the nucleotide-excision repair (NER) pathway. There are at least eight core NER proteins participating in the pathway, and genetic variations in their genes may alter NER functions. We hypothesized that some NER variants are associated with risk of cutaneous melanoma. In a hospital-based case-control study of 602 non-Hispanic White patients with cutaneous melanoma and 603 age- and sex-matched cancer-free controls, we genotyped five common non-synonymous single-nucleotide polymorphisms identified to date and assessed their associations with risk of cutaneous melanoma. We found that a significantly increased risk of cutaneous melanoma was associated with XPD 751Lys/Gln [adjusted odds ratio (OR), 1.55 and 95% confidence interval (95% CI), 1.12-2.16] and XPD 751Gln/Gln (OR, 1.66; 95% CI, 1.03-2.68) genotypes compared with the XPD 751Lys/Lys genotype as well as XPD312Asp/Asn (OR, 1.54; 95% CI, 1.11-2.12) and XPD312Asn/Asn (OR, 1.75; 95% CI, 1.05-2.90) genotypes compared with the XPD 312Asp/Asp genotype. This increased risk was not observed in the other three XPC and XPG single-nucleotide polymorphisms. Moreover, the number of the observed XPD at-risk genotypes (i.e., 312Asn/Asn+Asn/Asp and 751Gln/Gln+Lys/Gln) was associated with cutaneous melanoma risk in a dose-response manner (OR, 1.47; 95% CI, 0.97-2.23 for one at-risk genotype; OR, 1.83; 95% CI, 1.29-2.61 for two at-risk genotypes; Ptrend < 0.001). However, we found no evidence of any interaction between XPD genotypes with XPC and XPG genotypes or the known risk factors. We concluded that genetic variants of the XPD gene might serve as biomarkers for susceptibility to cutaneous melanoma. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2526–32)

Genetic polymorphisms in DNA base-excision repair genes ADPRT, XRCC1, and APE1 and the risk of squamous cell carcinoma of the head and neck

Tobacco smoke contains numerous carcinogens that cause DNA damage, including oxidative lesions that are removed effectively by the base‐excision repair (BER) pathway, in which adenosine diphosphate ribosyl transferase (ADPRT), x‐ray repair cross‐complementing 1 (XRCC1), and apurinic/apyimidinic endonuclease (APE1) play key roles. Genetic variations in the genes encoding for these DNA repair enzymes may alter their functions. Although there have been several studies that generated mixed results on the association between XRCC1 variants and the risk of squamous cell carcinoma of the head and neck (SCCHN), no reported studies have investigated the association between ADPRT and APE1 variants and SCCHN risk.

Polymorphisms of Methionine Synthase and Methionine Synthase Reductase and Risk of Squamous Cell Carcinoma of the Head and Neck: a Case-Control Analysis

Although tobacco and alcohol use are the major risk factors, folate deficiency has been implicated in the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of methionine synthase (MTR) and methionine synthase reductase (MTRR) in the folate matabolic pathway are associated with SCCHN risk. In a hospital-based case-control study of 721 SCCHN cases and 1,234 controls of non-Hispanic Whites, frequency matched by age, sex, and smoking status, we genotyped the MTR A2756G and MTRR G66A polymorphisms. We found that the MTR variant AG and AG/GG genotypes were associated with a significantly increased SCCHN risk [adjusted odd ratio (OR), 1.31; 95% confidence interval (95% CI), 1.07-1.60 for AG and OR, 1.28; 95% CI, 1.05-1.56 for AG/GG] compared with the AA genotype. In contrast, the MTRR variant AA genotype was associated with a significantly decreased SCCHN risk (OR, 0.68; 95% CI, 0.52-0.90) compared with the 66GG genotype. When the two polymorphisms were evaluated together by the number of risk alleles, the SCCHN risk was significantly increased in a dose-dependent manner (Ptrend = 0.002). The risk of SCCHN was 1.47 (95% CI, 1.08-1.99) for one risk allele, 1.67 (95% CI, 1.23-2.27) for two risk alleles, and 1.74 (95% CI, 1.18-2.54) for three or four risk alleles compared with the wild-type (0 risk allele) genotype. In conclusion, our data provide evidence that support the association between the MTR A2756G and MTRR G66A polymorphisms and SCCHN risk and that these two polymorphisms may have a joint effect on risk of SCCHN.

Polymorphisms of the DNMT3B gene and risk of squamous cell carcinoma of the head and neck: A case-control study

DNA-methyltransferase-3B (DNMT3B) may play an oncogenic role during tumorigenesis, and its genetic variants have been reportedly to be associated with risk of several cancers, but few studies have investigated their roles in squamous cell carcinoma of the head and neck cancer (SCCHN). Here we report a hospital-based case-control study with 832 SCCHN patients and 843 cancer-free controls of non-Hispanic whites that evaluated the association between two DNMT3B single nucleotide polymorphisms (SNPs) DNMT3B -149C>T (rs2424913) and DNMT3B -579G>T (rs2424909) in the promoter region and risk of SCCHN. We found that compared with C-allele carriers, the DNMT3B -149 TT genotype was statistically significantly associated with increased risk of SCCHN (adjusted OR, 1.35, 95% CI, 1.01-1.80, P=0.043), whereas the DNMT3B -579 TT genotype showed only a non-statistically significant risk compared with G-allele carriers. Further analysis of the effects of combined genotypes suggested that subjects with either DNMT3B -149 TT or DNMT3B -579 TT homozygous genotypes had statistically significantly increased risk of SCCHN (adjusted OR=1.36, 95% CI=1.07-1.73, P=0.013). Stratification analysis showed a more profound risk in the subgroups of the young (< or =57 years, the median age of the controls), males, current smokers, current drinkers, and patients with primary tumor sites of pharynx and larynx. This large study provides reliable risk estimates for associations between DNMT3B variants and SCCHN risk in non-Hispanic whites, and our findings are consistent with that of previously reported cancer case-control studies of other cancers. Further mechanistic studies are needed to unravel the underlying molecular mechanisms.

Potentially functional single nucleotide polymorphisms in the core nucleotide excision repair genes and risk of squamous cell carcinoma of the head and neck.

Susceptibility to cancer has been associated with DNA repair capacity, a global reflection of all functional variants, most of which are relatively rare. Among the 1,098 single nucleotide polymorphisms (SNP) identified in the eight core nucleotide excision repair genes, only a few are common nonsynonymous or regulatory SNPs that are potentially functional. We tested the hypothesis that seven selected common nonsynonymous and regulatory variants in the nucleotide excision repair core genes are associated with risk of squamous cell carcinoma of the head and neck (SCCHN) in a hospital-based, case-control study of 829 SCCHN cases and 854 cancer-free controls. Assuming a recessive genetic model, we found that only carriers of the XPC 499Val/Val genotype had a significantly increased SCCHN risk (adjusted odds ratio, 1.65; 95% confidence interval, 1.16-2.36). In analysis of the joint effects, the number of observed risk genotypes was associated with SCCHN risk in a dose-response manner (P for trend = 0.017) and those who carried four or more risk genotypes exhibited a borderline significant 1.23-fold increased SCCHN risk (adjusted odds ratio, 1.23; 95% confidence interval, 0.99-1.53). In the stratified analysis, the dichotomized combined effect of the seven SNPs was slightly more evident among older subjects, women, and laryngeal cancer. These findings suggest that these potentially functional SNPs may collectively contribute to susceptibility to SCCHN. These findings need to be validated in larger, independent studies. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1633–8)

Methylenetetrahydrofolate reductase polymorphisms and risk of squamous cell carcinoma of the head and neck: A case-control analysis

Folate deficiency is implicated in cancer risk that may be modulated by a genetic variation in the methylenetetrahydrofolate reductase (MTHFR) gene in folate metabolism. We hypothesized that genetic variants in MTHFR are associated with risk of squamous cell carcinoma of the head and neck (SCCHN). We genotyped 3 MTHFR polymorphisms (C677T, A1298C and G1793A) and estimated their haplotypes in a hospital‐based case‐control study of 537 SCCHN cases and 545 cancer‐free controls. The controls were frequency‐matched to the cases by age (± 5 years), sex, ethnicity and smoking status. We found that the MTHFR 1298AC/CC genotypes were associated with an approximately 35% reduction in risk of SCCHN (adjusted odds ratio = 0.65; 95% CI = 0.51–0.82) compared to the AA genotype. The MTHFR 677CT and 1793GA/AA genotypes were associated with nonsignificant increased risk of SCCHN compared to the 677CC and 1793GG genotypes, respectively. We estimated that there were 8 haplotypes and 16 haplotype genotypes based on these 3 variants. When we used the haplotypes and assumed that the 677T, 1298A and 1793A alleles were risk alleles, the adjusted odds ratios increased as the number of risk alleles increased: 1.00 for 0–1 variant, 1.85 (1.3–2.5) for any 2 risk alleles and 1.93 (1.4–2.7) for any 3 risk alleles. These results suggest that all 3 MTHFR polymorphisms may play a role in the susceptibility to SCCHN among non‐Hispanic whites. Future studies should incorporate detailed data on alcohol consumption, dietary folate intake and related serologic measurements.

Haplotype and Genotypes of the VDR Gene and Cutaneous Melanoma Risk in Non-Hispanic Whites in Texas: A Case-Control Study

In a hospital‐based case–control study of 805 non‐Hispanic whites with cutaneous melanoma and 841 cancer‐free age‐, sex‐ and ethnicity‐matched control subjects, 3 VDR polymorphisms (i.e., TaqI, BsmI and FokI) were genotyped using blood samples collected between 1994 and 2006. We tested the hypothesis that the haplotypes and combined genotypes of these polymorphisms were associated with melanoma risk by interacting with known risk factors. Haplotypes t‐B‐F (adjusted odds ratio [OR], 0.52; 95% confidence interval [CI], 0.34–0.80) and t‐B‐f (adjusted OR, 0.51; CI, 0.27–0.94) were associated with a reduced risk when compared to T‐b‐f. The combined genotypes Tt+tt/Bb+BB/Ff+ff (adjusted OR, 0.69; CI, 0.52, 0.90) and Tt+tt/Bb+BB/FF (adjusted OR, 0.58; CI, 0.43, 0.78) were also associated with reduced risk, whereas the combined genotype TT/Bb+BB/Ff+ff genotype (adjusted OR, 2.35; CI, 1.13, 4.98) was associated with increased risk when compared to TT/bb/Ff+ff genotypes. On multivariate analysis, only the TaqI polymorphism was an independent risk factor, while the FokI polymorphism interacted with skin color (p = 0.029), moles (p = 0.017) and first‐degree relatives with any cancer (p = 0.013) in modifying risk. Together, these findings suggest that VDR polymorphisms may directly affect or modify the risk associated with known melanoma risk factors. Larger, population‐based studies are needed to replicate our findings.