Thirteen tag SNPs at the CASP8 and CASP10 loci in patients with advanced NSCLC were genotyped in a two-stage analysis consisting of a discovery set and an independent validation set. These SNPs were evaluated for their association with toxicity outcomes with platinum-based chemotherapy.
Caspase-8 and caspase-10 play crucial roles in both cancer development and chemotherapy efficacy. In this study, we aimed to comprehensively assess single nucleotide polymorphisms (SNPs) of the caspase-8 (CASP8) and caspase-10 (CASP10) genes in relation to toxicity outcomes with first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 13 tag SNPs of CASP8 and CASP10 in 663 patients with advanced NSCLC treated with platinum-based chemotherapy regimens. Associations between SNPs and chemotherapy toxicity outcomes were identified in a discovery set of 279 patients and then validated in an independent set of 384 patients. In both the discovery and validation sets, variant homozygotes of CASP8 rs12990906 and heterozygotes of CASP8 rs3769827 and CASP10 rs11674246 and rs3731714 had a significantly lower risk for severe toxicity overall. However, only the association with the rs12990906 variant was replicated in the validation set for hematological toxicity risk. In a stratified analysis, we found that some other SNPs, including rs3769821, rs3769825, rs7608692, and rs12613347, were significantly associated with severe toxicity risk in some subgroups, such as in nonsmoking patients, patients with adenocarcinoma, and patients treated with cisplatin combinations. Consistent results were also found in haplotype analyses. Our results provide novel evidence that polymorphisms in CASP8 and CASP10 may modulate toxicity outcomes in patients with advanced NSCLC treated with platinum-based chemotherapy. If validated, the findings will facilitate the genotype-based selection of platinum-based chemotherapy regimens.
CASP8; CASP10; Polymorphisms; Platinum-based chemotherapy; Toxicity; Non-small cell lung cancer; Association
High altitude acclimatization is a series of physiological responses taking places when subjects go to altitude. Many factors could influence these processes, such as altitude, ascending speed and individual characteristics. In this study, based on a repeated measurement design of three sequential measurements at baseline, acute phase and chronic phase, we evaluated the effect of BMI, smoking and drinking on a number of physiological responses in high altitude acclimatization by using mixed model and partial least square path model on a sample of 755 Han Chinese young males. We found that subjects with higher BMI responses were reluctant to hypoxia. The effect of smoking was not significant at acute phase. But at chronic phase, red blood cell volume increased less while respiratory function increased more for smoking subjects compared with nonsmokers. For drinking subjects, red blood cell volume increased less than nondrinkers at both acute and chronic phases, while blood pressures increased more than nondrinkers at acute phase and respiratory function, red blood cell volume and oxygen saturation increased more than nondrinkers at chronic phase. The heavy and long-term effect of smoking, drinking and other factors in high altitude acclimatization needed to be further studied.
To mine possibly hidden causal single nucleotide polymorphisms (SNPs) in the etiology of melanoma, we investigated the association of SNPs in 76 M/G1 transition genes with melanoma risk using our published genome-wide association study (GWAS) dataset with 1804 melanoma cases and 1,026 cancer-free controls. We found multiple SNPs with P < 0.01 and performed validation studies for 18 putative functional SNPs in PSMB9 in other two GWAS datasets. Two SNPs (rs1351383 and rs2127675) were associated with melanoma risk in the GenoMEL dataset (P = 0.013 and 0.004, respectively), but failed validation in the Australia dataset. Genotype-phenotype analysis revealed these two SNPs were significantly correlated with mRNA expression levels of PSMB9. Further experiments revealed that the promoter SNP rs2071480, which is in high LD with rs1351383 and rs2127675, involved in influencing transcription factor binding and gene expression. Taken together, our data suggested that functional variants in PSMB9 may contribute to melanoma susceptibility.
GWAS; Cell cycle; PSMB9; Polymorphism; melanoma
Lung cancer is a complex polygenic disease. Although recent genome-wide association (GWA) studies have identified multiple susceptibility loci for lung cancer, most of these variants have not been validated in a Chinese population. In this study, we investigated whether a genetic risk score combining multiple.
Five single-nucleotide polymorphisms (SNPs) identified in previous GWA or large cohort studies were genotyped in 5068 Chinese case–control subjects. The genetic risk score (GRS) based on these SNPs was estimated by two approaches: a simple risk alleles count (cGRS) and a weighted (wGRS) method. The area under the receiver operating characteristic (ROC) curve (AUC) in combination with the bootstrap resampling method was used to assess the predictive performance of the genetic risk score for lung cancer.
Four independent SNPs (rs2736100, rs402710, rs4488809 and rs4083914), were found to be associated with a risk of lung cancer. The wGRS based on these four SNPs was a better predictor than cGRS. Using a liability threshold model, we estimated that these four SNPs accounted for only 4.02% of genetic variance in lung cancer. Smoking history contributed significantly to lung cancer (P < 0.001) risk [AUC = 0.619 (0.603-0.634)], and incorporated with wGRS gave an AUC value of 0.639 (0.621-0.652) after adjustment for over-fitting. This model shows promise for assessing lung cancer risk in a Chinese population.
Our results indicate that although genetic variants related to lung cancer only added moderate discriminatory accuracy, it still improved the predictive ability of the assessment model in Chinese population.
Chinese; Cumulative risk; Genetic risk score; Lung cancer; Risk assessment
RAD52 is an important but not well characterized homologous recombination repair gene that can bind to single-stranded DNA ends and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. To evaluate the role of RAD52 variants in the response of tumor cells to platinum agents, we investigated their associations with platinum resistance and prognosis in cervical cancer patients. We enrolled 154 patients with cervical squamous cell carcinoma, who had radical surgery between 2008 and 2009, and genotyped three potentially functional RAD52 variants by the SNaPshot assay. We tested in vitro platinum resistance and RAD52 expression by using the MTT and immunohistochemistry methods, respectively. In 144 cases who had genotyping data, we found that both the rs1051669 variant and RAD52 protein expression were significantly associated with carboplatin resistance (P = 0.024 and 0.028, respectively) and rs10774474 with nedaplatin resistance (P = 0.018). The rs1051669 variant was significantly associated with RAD52 protein expression (adjusted OR = 4.7, 95% CI = 1.4−16.1, P = 0.013). When these three RAD52 variants were combined, progression-free survival was lower in patients who carried at least one (≥1) variant allele compared to those without any of the variant alleles (P = 0.047). Therefore, both RAD52 variants and protein expression can predict platinum resistance, and RAD52 variants appeared to predict prognosis in cervical cancer patients. Large studies are warranted to validate these findings.
Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)–related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV–related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV–positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10−19) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10−8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10−4; rs455804: OR = 0.84, P = 6.92×10−3). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Previous studies strongly suggest the importance of genetic susceptibility for hepatocellular carcinoma (HCC). However, the studies about genetic etiology on HBV–related HCC were limited. Our genome-wide association study included 523,663 autosomal SNPs in 1,538 HBV–positive HCC patients and 1,465 chronic HBV carriers for the discovery analysis. 2,112 HBV–positive HCC cases and 2,208 HBV carriers (the initial validation), and 1,021 cases and 1,491 HBV carriers (the second validation), were then analyzed for validation. The fourth independent samples of 1,298 cases and 1,026 controls were analyzed as replication. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 and rs455804 (GRIK1) on 21q21.3. HLA-DRB1 molecules play an important role in chronic HBV infection and progression to HCC. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV–related HCC, suggesting the involvement of glutamate signaling in the development of HBV–related HCC.
Xeroderma pigmentosum group D (XPD) codes for a DNA helicase involved in nucleotide excision repair that removes platinum-induced DNA damage. Genetic polymorphisms of XPD may affect DNA repair capacity and lead to individual differences in the outcome of patients after chemotherapy. This study aims to identify whether XPD polymorphisms affect clinical efficacy among advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
353 stage III-IV NSCLC patients receiving platinum-based chemotherapy as the first-line treatment were enrolled in this study. Four potentially functional XPD polymorphisms (Arg156Arg, Asp312Asn, Asp711Asp and Lys751Gln) were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or PCR-based sequencing.
Variant genotypes of XPD Asp312Asn, Asp711Asp and Lys751Gln were significantly associated with poorer NSCLC survival (P = 0.006, 0.006, 0.014, respectively, by log-rank test). The most common haplotype GCA (in order of Asp312Asn, Asp711Asp and Lys751Gln) also exhibited significant risk effect on NSCLC survival (log-rank P = 0.001). This effect was more predominant for patients with stage IIIB disease (P = 2.21×10−4, log-rank test). Increased risks for variant haplotypes of XPD were also observed among patients with performance status of 0–1 and patients with adenocarcinoma. However, no significant associations were found between these polymorphisms, chemotherapy response and PFS.
Our study provides evidence for the predictive role of XPD Asp312Asn, Asp711Asp and Lys751Gln polymorphisms/haplotype on NSCLC prognosis in inoperable advanced NSCLC patients treated with platinum-based chemotherapy.
Recent genome-wide association studies (GWAS) have found a single nucleotide polymorphism (SNP, rs2274223 A>G) in PLCE1 to be associated with risk of gastric adenocarcinoma. In the present study, we validated this finding and also explored the risk associated with another unreported potentially functional SNP (rs11187870 G>C) of PLCE1 in a hospital-based case-control study of 1059 patients with pathologically confirmed gastric adenocarcinoma and 1240 frequency-matched healthy controls.
We determined genotypes of these two SNPs by the Taqman assay and used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). We found that a significant higher gastric adenocarcinoma risk was associated with rs2274223 variant G allele (adjusted OR = 1.35, 95% CI = 1.14–1.60 for AG+GG vs. AA) and rs11187870 variant C allele (adjusted OR = 1.26, 95% CI = 1.05–1.50 for CG+CC vs. GG). We also found that the number of combined risk alleles (i.e., rs2274223G and rs11187870C) was associated with risk of gastric adenocarcinoma in an allele-dose effect manner (Ptrend = 0.0002). Stratification analysis indicated that the combined effect of rs2274223G and rs11187870C variant alleles was more evident in subgroups of males, non-smokers, non-drinkers and patients with gastric cardia adenocarcinoma. Further real-time PCR results showed that expression levels of PLCE1 mRNA were significantly lower in tumors than in adjacent noncancerous tissues (0.019±0.002 vs. 0.008±0.001, P<0.05).
Our results further confirmed that genetic variations in PLCE1 may contribute to gastric adenocarcinoma risk in an eastern Chinese population.
The population of Han Chinese is ∼1.226 billion people. Genetic heterogeneity between northern Han Chinese (N-Han) and southern Han Chinese (S-Han) has been demonstrated by recent genome-wide studies. As an initial step toward health disparities and personalized medicine in Chinese population, this study developed a set of ancestry informative markers (AIM) for Han Chinese population.
ancestry informative marker; Han Chinese; genetic association study; population structure
The 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.
We 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).
We 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 (N2-3 vs. N0-1: HR = 1.60, 95% CI = 1.09-2.35) and tumor stage (T3-4 vs. T0-2: HR = 1.48, 95% CI = 1.08-2.03).
Although 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.
TNF-α; TNFRSF1B; polymorphism; non-small cell lung cancer; survival
Vinyl chloride (VC) was classified as a group 1 carcinogen by IARC in 1987. Although the relationship between VC exposure and liver cancer has been established, the mechanism of VC-related carcinogenesis remains largely unknown. Previous epidemiological studies have shown that VC exposure is associated with increased genotoxicity in humans. To explore chromosomal damage and its progression, and their association to genetic susceptibility, we investigated 402 workers exposed to VC, a 77 VC-exposed cohort and 141 unexposed subjects. We measured the frequencies of cytokinesis-block micronucleus (CBMN) to reflect chromosomal damage and conducted genotyping for six xenobiotic metabolisms and five DNA repair genes' polymorphism. Data indicate that 95% of the control workers had CBMN frequencies ≤3‰, whereas VC-exposed workers had the 3.73-fold increase compared with the controls. Among the cohort workers who were followed from 2004 to 2007, the mean CBMN frequency was higher in 2007 than in 2004 with ratio of 2.08. Multiple Poisson regression analysis showed that mean CBMN frequencies were significantly elevated for the intermediate and high exposure groups than the low. Exposed workers with CYP2E1 or XRCC1 variance showed a higher CBMN frequency than their wild-type homozygous counterparts, so did workers with GSTP1 or ALDH2 genotype. This study provides evidence that cumulative exposure dose of VC and common genetic variants in genes relevant to detoxification of carcinogens are the major factors that modulate CBMN induction in VC-exposed workers.
The AZFc region on the human Y chromosome has been found to be functionally important in spermatogenesis. Complete AZFc deletion is one of the most frequent causes of male infertility and the roles of partial AZFc deletions (gr/gr and b2/b3 deletions) in spermatogenesis are controversial.
To further study the roles of partial AZFc deletions in spermatogenic impairment and the relationship between complete and partial AZFc deletions, these deletions were typed and quantitative analysis of DAZ gene copies and Y chromosome haplogrouping were performed for seven pedigrees of complete AZFc deletion carriers, comprising 296 infertile and 280 healthy Chinese men.
Neither the gr/gr nor the b2/b3 deletion was found to be associated with spermatogenic failure. In one pedigree, a complete AZFc deletion was observed to result from the gr/gr deletion, suggesting that complete deletions of AZFc can be preceded by partial deletions. In addition, a new gr/gr‐deleted Y haplogroup Q1 was identified and the reported fixation of the b2/b3 deletion in haplogroup N confirmed. The frequency of complete AZFc deletion in haplogroups Q1 and N was significantly higher than that in the other haplogroupsm with fewer partial deletions. Duplications of DAZ gene copies were also observed in this study.
To date, these observations comprise the first evidence showing that partial AZFc deletions can increase the risk of complete AZFc deletion. The susceptibility of partial AZFc deletions to complete AZFc deletion deserves further examination, especially in the populations or Y haplogroups abundant in partial AZFc deletions.
Y chromosome; AZFc deletion, haplogroup; male infertility; spermatogenesis
Epidermal growth factor (EGF) is critical in cancer process. EGF and EGF receptor (EGFR) interaction plays a pivotal role in cell proliferation, differentiation, and tumorigenesis of epithelial tissues. Variations of the EGF +61G/A (rs4444903) may lead to an alteration in EGF production and/or activity, which can result in individual susceptibility to brain glioma. The purpose of this study was to investigate the potential association between EGF +61G/A and brain glioma in a Chinese population.
In this study, we analyzed single nucleotide polymorphism of EGF +61G/A in 677 patients with glioma and 698 gender- and age-matched controls. Genotyping was performed by polymerase chain reaction-ligation detection reaction (PCR-LDR) method.
The A allele (minor Allele) was 33.0% in cases and 27.3% in controls. The additive model was more powerful to reveal the association in our study than that of recessive and dominant model. Our data showed the genotype G/A and A/A was associated with increased risk for glioma (adjusted OR = 1.48, 95%CI: 1.17-1.87, p = 0.001 for G/A, adjusted OR = 1.81, 95%CI: 1.20-2.72, p = 0.005 for A/A, respectively), and for glioblastoma (adjusted OR = 1.51, 95%CI: 1.06-2.17, p = 0.024 and adjusted OR = 2.35, 95%CI: 1.34-4.15, p = 0.003, respectively). The A allele significantly increased glioma risk (OR = 1.31, 95%CI: 1.11-1.55, p = 0.001). The additive model (G/G vs G/A vs A/A) showed that both G/A and A/A genotype increased glioma risk (adjusted OR = 1.40, 95% CI: 1.17-1.66, p = 0.0002).G/A and A/A genotypes or EGF +61 A allele increased risk in both low and high WHO grade glioma. Non-smokers with G/A and A/A genotype showed increased glioma risk compared with G/G genotype (adjusted OR = 1.72, 95%CI: 1.29-2.30, p = 0.0002 and adjusted OR = 1.81, 95%CI: 1.10-2.99, p = 0.020, respectively). This association was not found in ever- or current-smokers.
Our study indicated that G/A and A/A genotypes or EGF +61 A allele were associated with higher glioma risk in Chinese. This is in contrast with previous studies which reported G allele as a risk factor of glioma in Caucasian. The role of EGF +61 A/G polymorphism in glioma susceptibility needs further investigation.
Longevity is a multifactorial trait with a genetic contribution, and mitochondrial DNA (mtDNA) polymorphisms were found to be involved in the phenomenon of longevity.
To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population based case-control study was conducted in Rugao – a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged ≥95 yr (EL group). Control subjects include 926 individuals aged 60–69 years (elderly group) and 463 individuals aged 40–49 years (middle-aged group) randomly recruited from Rugao. We observed significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%) and longevity subjects (4.8%) (p = 0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%) and longevity subjects (21.7%) in females (p = 0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%) and longevity subjects (1.7%) in females (p = 0.045).
Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population.
Rapid economic growth in China in the past decades has been accompanied by dramatic changes in lifestyle and environmental exposures. The burdens of non-communicable diseases, such as cardiovascular diseases, diabetes and cancer, have also increased substantially.
We initiated a large prospective cohort–the Taizhou Longitudinal Study–in Taizhou (a medium-size city in China) to explore the environmental and genetic risk factors for common non-communicable diseases. The sample size of the cohort will be at least 100,000 adults aged 30–80 years drawn from the general residents of the districts of Hailin, Gaogang, and Taixing (sample frame, 1.8 million) of Taizhou. A three-stage stratified sampling method will be applied. Baseline investigations include interviewer-administered questionnaire, anthropometric measurements, and collection of buccal mucosal cells and blood specimens. DNA will be extracted for genetic studies and serum samples will be used for biochemical examinations. A follow-up survey will be conducted every three years to obtain information on disease occurrence and information on selected lifestyle exposures. Study participants will be followed-up indefinitely by using a chronic disease register system for morbidity and cause-specific mortality. Information on non-fatal events will be obtained for certain major categories of disease (e.g., cancer, stroke, myocardial infarction) through established registry systems.
The Taizhou Longitudinal Study will provide a good basis for exploring the roles of many important environmental factors (especially those concomitant with the economic transformation in China) for common chronic diseases, solely or via interaction with genetic factors.
Class C G protein-coupled receptors (GPCRs) represent a distinct group of the GPCR family, which structurally possess a characteristically distinct extracellular domain inclusive of the Venus flytrap module (VFTM). The VFTMs of the class C GPCRs is responsible for ligand recognition and binding, and share sequence similarity with bacterial periplasmic amino acid binding proteins (PBPs). An extensive phylogenetic investigation of the VFTMs was conducted by analyzing for functional divergence and testing for positive selection for five typical groups of the class C GPCRs. The altered selective constraints were determined to identify the sites that had undergone functional divergence via positive selection. In order to structurally demonstrate the pattern changes during the evolutionary process, three-dimensional (3D) structures of the GPCR VFTMs were modelled and reconstructed from ancestral VFTMs.
Our results show that the altered selective constraints in the VFTMs of class C GPCRs are statistically significant. This implies that functional divergence played a key role in characterizing the functions of the VFTMs after gene duplication events. Meanwhile, positive selection is involved in the evolutionary process and drove the functional divergence of the VFTMs. Our results also reveal that three continuous duplication events occurred in order to shape the evolutionary topology of class C GPCRs. The five groups of the class C GPCRs have essentially different sites involved in functional divergence, which would have shaped the specific structures and functions of the VFTMs.
Taken together, our results show that functional divergence involved positive selection and is partially responsible for the evolutionary patterns of the class C GPCR VFTMs. The sites involved in functional divergence will provide more clues and candidates for further research on structural-function relationships of these modules as well as shedding light on the activation mechanism of the class C GPCRs.
Multiplexing technologies, which allow for simultaneous detection of multiple nucleic acid sequences in a single reaction, can save a lot of time, cost and labor compared to traditional single reaction detection methods. However, the multiplexing method currently used requires precise handiwork and many complicated steps, making a new, simpler technique desirable. Oligonucleotides containing locked nucleic acid residues are an attractive tool because they have strong affinities for their complementary targets, they have been used to avoid dimer formation and mismatch hybridization and to enhance efficient priming. In this study, we aimed to investigate the use of locked nucleic acid pentamers for genomic DNA amplification and multiplex genotyping.
We designed locked nucleic acid pentamers as universal PCR primers for genomic DNA amplification. The locked nucleic acid pentamers were able to prime amplification of the selected sequences within the investigated genomes, and the resulting products were similar in length to those obtained by restriction digest. In Real Time PCR of genomic DNA from three bacterial species, locked nucleic acid pentamers showed high priming efficiencies. Data from bias tests demonstrated that locked nucleic acid pentamers have equal affinities for each of the six genes tested from the Klebsiella pneumoniae genome. Combined with suspension array genotyping, locked nucleic acid pentamer-based PCR amplification was able to identify a total of 15 strains, including 3 species of bacteria, by gene- and species-specific probes. Among the 32 species used in the assay, 28 species and 50 different genes were clearly identified using this method.
As a novel genomic DNA amplification, the use of locked nucleic acid pentamers as universal primer pairs in conjunction with suspension array genotyping, allows for the identification of multiple distinct genes or species with a single amplification procedure. This demonstrates that locked nucleic acid pentamer-based PCR can be utilized extensively in pathogen identification.
The nucleotide excision repair (NER) protein, xeroderma pigmentosum C (XPC), participates in recognizing DNA lesions and initiating DNA repair in response to DNA damage. Because mutations in XPC cause a high risk of cancer in XP patients, we hypothesized that inherited sequence variations in XPC may alter DNA repair and thus susceptibility to cancer.
In this hospital-based case-control study, we investigated five XPC tagging, common single nucleotide polymorphisms (tagging SNPs) in 1,010 patients with newly diagnosed lung cancer and 1,011 matched cancer free controls in a Chinese population.
In individual tagging SNP analysis, we found that rs3731055AG+AA variant genotypes were associated with a significantly decreased risk of lung adenocarcinoma [adjusted odds ratio (OR), 0.71; 95% confidence interval (CI), 0.56–0.90] but an increased risk of small cell carcinomas [adjusted OR, 1.79; 95% CI, 1.05–3.07]. Furthermore, we found that haplotype ACCCA was associated with a decreased risk of lung adenocarcinoma [OR, 0.78; 95% CI, 0.62–0.97] but an increased risk of small cell carcinomas [OR, 1.68; 95% CI, 1.04–2.71], which reflected the presence of rs3731055A allele in this haplotype. Further stratified analysis revealed that the protective effect of rs3731055AG+AA on risk of lung adenocarcinoma was more evident among young subjects (age ≤ 60) and never smokers.
These results suggest that inherited sequence variations in XPC may modulate risk of lung cancer, especially lung adenocarcinoma, in Chinese populations. However, these findings need to be verified in larger confirmatory studies with more comprehensively selected tagging SNPs.