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Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been suggested to play roles in various diseases, yet there is little data on their changes in patients with non-small-cell lung cancer (NSCLC). A simple LC-MS/MS method for EPA and DHA determination is critical to exploring EPA and DHA level changes in NSCLC patients.25 µL of serum was mixed with 25 µL of internal standard working solution, and then 450 µL of acetonitrile for protein precipitation. After vortex and centrifugation, the supernatant was directly used for LC-MS/MS analysis. The method was well validated with linearity, precision, recovery, and matrix effect. The concentrations of EPA and DHA in serum samples from 211 NSCLC patients and 227 healthy controls were determined by this LC-MS/MS method.Good separation and reliable quantification of EPA and DHA in serum samples were achieved by our method. Compared with healthy controls, serum EPA and DHA were significantly reduced in both adenocarcinoma and squamous cell carcinoma patients. The concentrations of EPA and DHA showed a progressive decrease in healthy controls, early- and advanced-stage NSCLC patients.This study identified significant reductions in serum EPA and DHA in NSCLC patients through the development of an LC-MS/MS method.

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42–2.21, p = 3.16 × 10(−7); P(multiplicative-interaction) = 1.20 × 10(−22); P(additive-interaction) = 6.50 × 10(−3)). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-β, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.

Bisphenol A (BPA), a common endocrine disrupter, can be activated by cytochrome P450 (CYP) metabolizing enzymes and might influence the development of breast cancer (BC). We hypothesized that BPA could interact with CYP genes, synergistically contributing to the BC risk.Urinary BPA was measured in a total of 302 newly diagnosed BC patients and 302 healthy controls by ultra-high performance liquid chromatography-high resolution mass spectrometry. A set of seven CYP gene polymorphisms was genotyped by using the Sequenom MassARRAY system. A multivariate logistic regression model was used to assess the associations of BPA and BPA-SNP interaction with BC risk.BC patients had a higher urinary BPA concentration than healthy individuals (P 0.001). Each 1-unit increase in log-transformed urinary BPA was associated with a 54 % increased BC risk [95 % confidence interval (CI), 1.34-1.77, P 0.001]. Individuals with the CYP19A1 rs1902580 GA + AA genotype showed a significantly higher BC risk than those with the GG genotype (OR = 1.45, 95 % CI, 1.01-2.09, P 0.05). A significant BPA-CYP17A1 rs743572 interaction was found to be associated with a higher risk of BC (PThe positive association of BPA exposure with BC risk might be modified by CYP17A1 rs743572, providing evidence for the interaction effect of environment-genes on the etiology of BC.

Multiple single nucleotide polymorphisms (SNPs) have been found to be highly correlated with colorectal cancer (CRC) risk. However, the variants identified thus far only explain a small part of the cases, suggesting the existence of many uncharacterised genetic determinants. In this study, using the multilevel 'omics' data provided in The Cancer Genome Atlas, we systematically performed expression quantitative trait locus (eQTL) analysis for CRC and identified nine SNPs with significant effects on mRNA expression (correlation |r| > 0.3 and FDR

Humans are extensively exposed to polycyclic aromatic hydrocarbons (PAHs) daily via multiple pathways. Epidemiological studies have demonstrated that occupational exposure to PAHs increases the risk of lung cancer, but related studies in the general population are limited. Hence, we conducted a case-control study among the Chinese general population to investigate the associations between PAHs exposure and lung cancer risk and analyze the modifications of genetic polymorphisms in DNA repair genes. In this study, we enrolled 122 lung cancer cases and 244 healthy controls in Wuhan, China. Urinary PAHs metabolites were determined by gas chromatography-mass spectrometry, and rs25487 in X-ray repair cross-complementation 1 (XRCC1) gene was genotyped by the Agena Bioscience MassARRAY System. Then, multivariable logistic regression models were performed to estimate the potential associations. We found that urinary hydroxynaphthalene (OH-Nap), hydroxyphenanthrene (OH-Phe) and the sum of hydroxy PAHs (∑OH-PAHs) levels were significantly higher in lung cancer cases than those in controls. After adjusting for gender, age, BMI, smoking status, smoking pack-years, drinking status and family history, urinary ∑OH-Nap and ∑OH-Phe levels were positively associated with lung cancer risk, with dose-response relationships. Compared with those in the lowest tertiles, individuals in the highest tertiles of ∑OH-Nap and ∑OH-Phe had a 2.13-fold (95% CI: 1.10, 4.09) and 2.45-fold (95% CI: 1.23, 4.87) increased risk of lung cancer, respectively. Effects of gender, age, smoking status and smoking pack-years on the associations of PAHs exposure with lung cancer risk were shown in the subgroup analysis. Furthermore, associations of urinary ∑OH-Nap and ∑OH-PAHs levels with lung cancer risk were modified by XRCC1 rs25487 (Pinteraction ≤ 0.025), and were more pronounced in wild-types of rs25487. These findings suggest that environmental exposure to naphthalene and phenanthrene is associated with increased lung cancer risk, and polymorphism of XRCC1 rs25487 might modify the naphthalene exposure-related lung cancer effect.

Biliary atresia (BA) is a major neonatal cholestatic disease and main indication for pediatric liver transplantation in the world. Recently, GPC1 has been implicated as a risk gene for BA by genetic studies and follow-up functional experiments on zebrafish.Two common genetic variants of GPC1, rs2292832 and rs3828336, were selected systematically through 'SNPinfo', and were examined using TaqMan Genotyping Assays for association studies in a Chinese population containing 134 cases and 618 controls.Of the two single nucleotide polymorphisms (SNPs), we found a significantly decreased BA risk associated with rs2292832 (additive model: OR=0.638, 95% CI: 0.467-0.873, P=0.005), and a marginal effect for rs3828336 (heterozygous model: OR=0.564, 95% CI: 0.312-1.020, P=0.058). The haplotype analysis indicated that either Crs2292832-Crs3828336Trs3828336 or Trs2292832-Trs3828336 conferred a protective effect from BA (OR=0.569, 95% CI=0.414-0.783, P0.001; OR=0.528, 95% CI: 0.301-0.926, P=0.026). Moreover, bioinformatics analysis suggested that rs2292832 altered GPC1 expression via effect on transcription-factor-binding sites (TFBS) of upstream binding transcription factor (UBTF), as a regulatory DNA variation in Deoxyribonuclease I (DNase I) hypersensitive sites (DHSs).Common variants of GPC1 gene were genetically involved in BA risk.

Exosomes, derived from various biofluids, may serve as potential biomarkers for cancer early detection. Nevertheless, exosome clinical translation remains challenging due to the lack of reliable isolation and detection methods. Herein, we present a novel integrated microfluidic device specifically designed for isolation and in-situ detection of lung cancer-specific exosomes collected from patient's urine. The new device has been fabricated using polymethyl methacrylate (PMMA) and a nanoporous gold (Au) nanocluster membrane modified with the capture antibody. The second antibody-conjugated Au nanorod probe was then loaded to identify and quantify lung cancer-specific exosomes using a dark field microscope. AuNC-Exosome-AuR complex produces a significant scattering wavelength shift and an improved scattering intensity due to resonance Rayleigh scattering, which enables the ultrasensitive detection of exosomes with a LOD below 1000 particles/mL. The proteomic analysis revealed that the high-purity exosomes has been isolated by the device. We then validated this method with 500 μL urine samples from lung cancer patients and controls, which showed great promise for differentiating early-stage lung cancer patients from healthy individuals. Taken together, the presented method is fast and ultrasensitive and can be easily adapted for the isolation and detection of cancer specific exosomes from other malignant tumors.

Bisphenol A (BPA), a well-known endocrine disruptor, was reported to promote migration and invasion of lung cancer cells, but findings in human study is absent. A case-control study in Chinese population was conducted to evaluate the association between BPA exposure and non-small cell lung cancer (NSCLC), and explore the interaction between BPA exposure and estrogen-related genetic polymorphism on NSCLC. BPA concentrations were measured in urine samples using an UHPLC-MS method and rs2046210 in estrogen receptor α (ESR1) gene was genotyped by TaqMan genotyping system. Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association analyses. As a result, 615 NSCLC cases and 615 healthy controls were enrolled from Wuhan, central China. The mean age was 58.0 (SD: 7.9) years old for controls and 59.2 (SD: 8.8) years old for cancer cases. The creatinine-adjusted BPA levels were significantly higher in NSCLC cases than that in healthy controls (median: 0.97 vs 0.73 μg/L, P 0.001). Exposure to high levels of BPA was significantly associated with NSCLC (adjusted OR = 1.91, 95%CI: 1.39-2.62, P 0.001 for the highest quartile). We also observed a shallow concave dose-response relationship about the overall association between BPA and NSCLC. Moreover, interaction analyses showed that BPA exposure interacted multiplicatively with rs2046210, with a marginal P value (P = 0.049), to contribute to NSCLC. In conclusion, exposure to high levels BPA may be associated with NSCLC and the relationship may be modified by genetic polymorphism in ESR1.

Background Genome-wide association studies (GWAS) have identified 5p15.33 as a susceptible locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically studied. We intended to explore the associations between low-frequency variants on 5p15.33 and NSCLC using a next-generation sequencing based approach in this study. Methods We have acquisited the variation spectrum of 400 NSCLC patients on 5p15.33 by sequencing the targeted region before. Candidate variants were primarily selected by restricting the minor allele frequency (MAF 1–5%) and then by comparing their frequency in 400 NSCLC patients with 1008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were discovered and replicated in two case-control sets: discovery stage with 960 cases and 916 controls, and replication stage with 1596 cases and 1614 controls in total. Results Five low-frequency variants were selected as our candidates and subsequent association analyses showed that 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53–0.76, P = 3.80 × 10−7) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63–0.84, P = 2.00 × 10−5) in upstream of CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants. Conclusions We newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese Han population.

Background: The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer, but causal variants have not been fully investigated. We intended to explore functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility and their relationship with telomere length in Chinese population. Methods: We conducted a targeted sequencing at 5p15.33 with 400 patients. Comparing with genotypic frequency in 1000 Genomes Project, we selected candidate variants and validated their associations with NSCLC in 985 cases and 970 controls. The relationships between susceptibility SNPs and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays were performed to reveal potential mechanisms. Findings: we identified 1478 variants through targeted sequencing and selected 17 candidate variants. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95% CI: 1.18-1.52, P = 7.78 × 10-6 )，rs10054203 (OR = 1.29, 95% CI: 1.13-1.46, P = 1.37 × 10-4 )，rs2736107 (OR = 1.28, 95% CI: 1.11-1.47, P = 5.14 × 10-4 ) and rs2853677 (OR = 1.23, 95% CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Functional exploration characterized rs7726159 promoted TERT transcription through disrupting transcription factor binding. Interpretation: The functional polymorphism, rs7726159, confers lung cancer susceptibility by disturbing telomere biology. Our study illustrated the functional significance of this variant in lung cancer initiation, which provides a new insight into the important role of telomere dysfunction in tumor progression. Funding Statement: This work was supported by the National Natural Science Foundation of China (81572071). Declaration of Interests: The authors declare that they have no potential conflicts of interest. Ethics Approval Statement: Written informed consent was obtained from each individual, and this study was approved by the Institutional Review Board of the Tongji Medical College, HUST.