L. Su

Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib

The−216G/T, −191C/A, intron 1 and Arg497Lys epidermal growth factor receptor (EGFR) polymorphisms were evaluated in 92 advanced non-small-cell lung cancer patients treated with gefitinib, an EGFR tyrosine-kinase inhibitor. Improved progression free survival (PFS) was found in patients homozygous for the shorter lengths of intron 1 polymorphism (S/S; S=16 or fewer CA repeats; log-rank test (LRT) P=0.03) and for patients carrying any T allele of the −216G/T polymorphism (LRT, P=0.005). When considered together, patients with intron 1 S/S genotype and at least one T allele of −216G/T had improved PFS (LRT P=0.0006; adjusted hazard ratio (AHR), 0.60 (95% confidence interval, 0.36–0.98)) and overall survival (LRT P=0.02; AHR, 0.60 (0.36–1.00)) when compared with all others. The T allele of −216G/T was also associated with significantly higher rates of stable disease/partial response (P=0.01) and a significantly higher risk of treatment-related rash/diarrhea (P=0.004, multivariate model). EGFR intron 1 and –216G/T polymorphisms influence clinical outcomes in gefitinib-treated non-small-cell lung cancer patients.

In-home solid fuel use and cardiovascular disease: a cross-sectional analysis of the Shanghai Putuo study

BackgroundAlthough recent research evidence suggests an association between household air pollution from solid fuel use, such as coal or biomass, and cardiovascular events such as hypertension, little epidemiologic data are available concerning such exposure effects on cardiovascular endpoints other than hypertension. We explored the association between in-home solid fuel use and self-reported diagnoses of cardiovascular endpoints, such as hypertension, coronary heart disease (CHD), stroke, and diabetes.MethodsWe analyzed 14,068 Chinese adults, aged 18 years and older. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated using logistic regression models for the risk of each outcome after adjusting for potential confounders.ResultsThe use of solid fuel in home was significantly associated with an increased risk for hypertension (OR 1.70, 95% CI 1.40 to 2.07), CHD (OR 2.58, 95% CI 1.53 to 4.32), and diabetes (OR 2.48, 95% CI 1.59 to 3.86), after adjusting for potential confounders. Compared with individuals in the lowest tertile of the duration of solid fuel exposure, those in the highest tertile of the duration of solid fuel exposure had an increased odds of hypertension (OR 1.73, 95% CI 1.45 to 2.06), stroke (OR 1.87, 95% CI 1.03 to 3.38), and diabetes (OR 3.18, 95% CI 2.11 to 4.78).ConclusionsOur data suggest that in-home solid fuel exposure maybe associated with increased risk for hypertension, CHD, stroke, and diabetes in the Chinese adult population. Further large-scale longitudinal studies are warranted to confirm these findings.

Genetic variants associated with severe pneumonia in A/H1N1 influenza infection

The A/H1N1 influenza strain isolated in Mexico in 2009 caused severe pulmonary illness in a small number of exposed individuals. Our objective was to determine the influence of genetic factors on their susceptibility. We carried out a case–control association study genotyping 91 patients with confirmed severe pneumonia from A/H1N1 infection and 98 exposed but asymptomatic household contacts, using the HumanCVD BeadChip (Illumina, San Diego, CA, USA). Four risk single-nucleotide polymorphisms were significantly (p<0.0001) associated with severe pneumonia: rs1801274 (Fc fragment of immunoglobulin G, low-affinity IIA, receptor (FCGR2A) gene, chromosome 1; OR 2.68, 95% CI 1.69–4.25); rs9856661 (gene unknown, chromosome 3; OR 2.62, 95% CI 1.64–4.18); rs8070740 (RPA interacting protein (RPAIN) gene, chromosome 17; OR 2.67, 95% CI 1.63–4.39); and rs3786054 (complement component 1, q subcomponent binding protein (C1QBP) gene, chromosome 17; OR 3.13, 95% CI 1.89–5.17). All SNP associations remained significant after adjustment for sex and comorbidities. The SNPs on chromosome 17 were in linkage disequilibrium. These findings revealed that gene polymorphisms located in chromosomes 1 and 17 might influence susceptibility to development of severe pneumonia in A/H1N1 infection. Two of these SNPs are mapped within genes (FCGR2A, C1QBP) involved in the handling of immune complexes and complement activation, respectively, suggesting that these genes may confer risk due to increased activation of host immunity.

Second hand smoke, age of exposure and lung cancer risk

BACKGROUND Exposure to second hand smoke (SHS) has been identified as a risk factor for lung cancer for three decades. It is also known that the lung continues to grow from birth to adulthood, when lung growth stops. We hypothesize that after adjusting for active cigarette smoking, if SHS exposure took place during the period of growth, i.e. in the earlier part of life (0-25 years of age) the risk of lung cancer is greater compared to an exposure occurring after age 25. METHOD Second hand smoke exposure was self-reported for three different activities (leisure, work and at home) for this study population of 1669 cases and 1263 controls. We created variables that captured location of exposure and timing of first exposure with respect to a study participants age (0-25, >25 years of age). Multiple logistic regressions were used to study the association between SHS exposure and lung cancer, adjusting for age, gender and active smoking variables. RESULT For study participants that were exposed to SHS at both activities (work and leisure) and compared to one or no activity, the adjusted odds ratio (AOR) for lung cancer was 1.30 (1.08-1.57) when exposure occurred between birth and age 25 and 0.66 (0.21-1.57) if exposure occurred after age 25 years. Respective results for non-smokers were 1.29 (0.82-2.02) and 0.87 (0.22-3.38), and current and ex-smokers combined 1.28 (1.04-1.58) and 0.66 (0.15-2.85). CONCLUSION All individuals exposed to SHS have a higher risk of lung cancer. Furthermore, this study suggests that subjects first exposed before age 25 have a higher lung cancer risk compared to those for whom first exposure occurred after age 25 years.

Validation of chromogenic in situ hybridization for detection of EGFR copy number amplification in nonsmall cell lung carcinoma

Epidermal growth factor receptor (EGFR) gene copy number correlates with response to tyrosine kinase inhibitors in patients with nonsmall cell lung carcinoma. Fluorescence in situ hybridization (FISH), a standard methodology to detect EGFR copy number abnormalities in nonsmall cell lung carcinoma, is limited by instrumentation and cost. Chromogenic in situ hybridization (CISH) is an emerging alternative detection technique using light microscopy, but its utility in assessing EGFR copy number in lung cancer is not established. To address the utility of CISH, we studied paraffin-embedded nonsmall cell lung carcinoma specimens from 77 Taiwanese nonsmoking women treated by surgery alone. We recorded the number of signals per tumor cell nucleus, correlated EGFR copy number by CISH with FISH results, and used receiver operating characteristics to identify cut-off points for the CISH results. Tumors were classified as adenocarcinoma (n=28), mixed adenocarcinoma with bronchioloalveolar features (n=25), bronchioloalveolar carcinoma (n=2), squamous cell carcinoma (n=15), and adenosquamous carcinoma (n=7). By FISH, 29% of cases had no amplification, 18% had low polysomy, 35% had high polysomy, and 12% had gene amplification. EGFR copy number detected by CISH highly correlated with FISH (Spearman r=0.81, P<0.0001). We determined the optimal EGFR CISH cut-off points that discriminate between no amplification and low polysomy (2.8 signals, P=0.09); no amplification plus low polysomy and high polysomy plus gene amplification (4.5 signals, P<0.0001); and high polysomy and gene amplification (7.1 signals, P=0.0003). CISH is an alternative assay to FISH in determining EGFR copy number status that may contribute to stratification of patients with nonsmall cell lung carcinoma for clinical trials and identify a subset of patients that should be treated with tyrosine kinase inhibitors.

Comparison of squamous cell carcinoma and adenocarcinoma of the lung by metabolomic analysis of tissue–serum pairs

The prospect of establishing serum metabolomic profiles offers great clinical significance for its potential to detect human lung cancers at clinically asymptomatic stages. Patients with suspicious serum metabolomic profiles may undergo advanced radiological tests that are too expensive to be employed as screening tools for the mass population. As the first step to establishing such profiles, this study investigates correlations between tissue and serum metabolomic profiles for squamous cell carcinoma (SCC) and adenocarcinoma (AC) in the lungs of humans. Tissue and serum paired samples from 14 patients (five SCCs and nine ACs), and seven serum samples from healthy controls were analyzed with high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS (1)HMRS). Tissue samples were subjected to quantitative histological pathology analyses after MRS. Based on pathology results, tissue metabolomic profiles for the evaluated cancer types were established using principal component and canonical analyses on measurable metabolites. The parameters used to construct tissue cancer profiles were then tested with serum spectroscopic results for their ability to differentiate between cancer types and identify cancer from controls. In addition, serum spectroscopic results were also analyzed independent of tissue data. Our results strongly indicate the potential of serum MR spectroscopy to achieve the task of differentiating between the tested human lung cancer types and from controls.

Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis

Background: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). Methods: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. Results: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (⩾2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. Conclusion: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.

Smoking and the risk of lung cancer: susceptibility with GSTP1 polymorphisms.

Background: GSTP1 is a gene that helps detoxify foreign substances in the body. Functional polymorphisms of GSTP1 have been studied as risk factors for lung cancer. Past studies have compared the effect of the “at risk” polymorphism in two strata of smoking pack-years (usually defined by the median among controls). We examined the interaction between GSTP1 polymorphisms and cumulative exposure to smoking and their association with lung cancer risk. Methods: Data are from a large hospital-based case–control study of persons treated for primary lung cancer at the Massachusetts General Hospital since 1992. Controls were drawn from friends and nonrelated family members. We genotyped 1,042 cases and 1,161 controls for GSTP1 using polymerase chain reaction–restriction fragment length polymorphism techniques. Findings: The GSTP1 GG genotype approximately doubled the lung cancer risk associated with pack-years. This interaction was stronger among current smokers. At 26 pack-years (median among controls with a smoking history), the adjusted odds ratio for the association between pack-years and lung cancer risk was 13 (95% confidence interval = 6.5–25) among current smokers with the GSTP1 GG genotype compared with 6.1 (95% confidence interval = 4.9–7.5) among those with the GSTP1 AA genotype Conclusions: GSTP1 GG increases the lung cancer risk associated with pack-years of smoking.

Synergistic Effects of NAT2 slow and GSTM1 null Genotypes on Carcinogen DNA Damage in the Lung

Background: Polymorphisms in carcinogen detoxification enzymes, NAT2 and GSTM1, have been suggested as susceptibility factors for DNA damage and lung cancer. However, little information is available on DNA adduct burden in the lung tissue and polymorphisms in NAT2 and GST genes. We investigated the independent and combined effects of the metabolic gene polymorphisms of NAT2 and GSTs on DNA adduct formation in different tissues (lung and blood) in lung cancer patients. Methods: DNA adducts were measured in lung and blood by the 32P-postlabeling assay. Multiple regression models were used to assess adjusted percent change in DNA adduct levels associated with GST and NAT2 genotypes. Results: After adjusting for potential confounders, as well as for other GST gene variants, lung adduct levels significantly increased by 150.3% [95% confidence interval (95% CI), 35.4-362.6%] for the GSTM1 null and by 73.9% (95% CI, −3.2% to 212.4%) for the NAT2 slow acetylator genotype, respectively. No association was seen with polymorphisms of other GST genes such as GSTT1 and GSTP1. The high-risk group, the combined GSTM1 null plus NAT2 slow, had significantly enhanced levels of lung adducts by 295% (95% CI, 72.7-803.5%) over those associated with single genes, suggesting a synergistic effect on DNA damage in the target lung tissue. Conclusions: The increase in DNA adduct levels in lung is associated with the GSTM1 null and NAT2 slow genotypes alone or in combination. Impact: These results suggest that GSTM1 and NAT2 genotypes play an independent and interactive role in the formation of carcinogen DNA adduct in the lung. Cancer Epidemiol Biomarkers Prev; 19(6); 1492–7. ©2010 AACR.

Adiponectin Gene Polymorphisms and Acute Respiratory Distress Syndrome Susceptibility and Mortality

Rationale Adiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality. Methods Consecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 3′ untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases. Results After multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36–5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029). Conclusions A common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels.