Frequent DNA methylation changes in cancerous and noncancerous lung tissues from smokers with non-small cell lung cancer.

Cancer deaths account for nearly 10 million deaths worldwide each year, with lung cancer (LCa) as the leading cause of cancer-related death. Smoking is one of the major LCa risk factors, and tobacco-related carcinogens are potent mutagens and epi-mutagens. In the present study, we aimed to analyse smoking-related epigenetic changes in lung tissues from LCa cases. The study cohort consisted of paired LCa and noncancerous lung tissues (NLT) from 104 patients, 90 of whom were smokers or ex-smokers (i.e. ever smokers) at the time of diagnosis. DNA methylation status of tumour suppressor genes DAPK1, MGMT, p16, RASSF1 and RARB was screened by means of methylation-specific PCR (MSP) and further analysed quantitatively by pyrosequencing. Methylation of at least one gene was detected in 59% (61 of 104) of LCa samples and in 39% (41 of 104) of NLT. DAPK1 and RASSF1 were more frequently methylated in LCa than in NLT (P = 0.022 and P = 0.041, respectively). The levels of DNA methylation were higher in LCa than NLT at most of the analysed CpG positions. More frequent methylation of at least one gene was observed in LCa samples of ever smokers (63%, 57 of 90) as compared with never smokers (36%, 5 of 14; P = 0.019). In the ever smokers group, methylation of the genes also occurred in NLT, but was rare or absent in the samples of never smokers. Among the current smokers, RASSF1 methylation in LCa showed association with the number of cigarettes smoked per day (P = 0.017), whereas in NLT it was positively associated with the duration of smoking (P = 0.039). Similarly, p16 methylation in LCa of current smokers correlated with the larger number of cigarettes smoked per day (P = 0.047). Overall, DNA methylation changes were present in both cancerous and noncancerous tissues of LCa patients and showed associations with smoking-related parameters.

Malignant pleural mesothelioma in Finland: regional and gender variation.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare occupational cancer with a poor prognosis. Even with a multimodality treatment approach, the treatment outcomes remain unsatisfactory. The use of asbestos has been banned in most developed countries, but MPM continues to be a significant occupational disease also in these countries. Aim of this study is to identify modern epidemiology and assess equality in care. METHODS: Our study cohort consists of 1010 patients diagnosed with MPM in Finland during 2000-2012. The data were collected from the Finnish Cancer Registry, the National Workers' Compensation Center Registry and the National Registry of Causes of Death, Statistics Finland. RESULTS: Women were diagnosed a mean of 4.5 years later than males (p = .001), but survival did not differ (overall median survival 9.7 months). A workers' compensation claim was more common in males (OR 11.0 [95% CI 7.5-16.2]) and in regions with a major asbestos industry (OR 1.7 [95% CI 1.3-2.2]). One-year and three-year survivals did not differ regionally. Patients without chemotherapy treatment had an inferior survival (RR 1.8 [95% CI 1.5-2.0]). The initial survival benefit gained with pemetrexed was diluted at 51 months. CONCLUSIONS: MPM is a disease with a poor prognosis, although chemotherapy appears to improve survival time. Significant gender and regional variation exists among patients, with notable differences in diagnostic and treatment practices. Long-term outcomes with pemetrexed remain indeterminate. IMPACT: Emphasize centralized consult services for the diagnosis, treatment and support that patients receive for MPM, facilitating equal outcomes and compensation.

Asbestos-associated genome-wide DNA methylation changes in lung cancer.

Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 × 10-19 , mean change in beta [Δ] -0.09), GPR135 (FDR 1.87 × 10-8 , mean Δ -0.09) and TPO (FDR 8.58 × 10-5 , mean Δ -0.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.

Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing.

BACKGROUND: Asbestos is a carcinogen linked to malignant mesothelioma (MM) and lung cancer. Some gene aberrations related to asbestos exposure are recognized, but many associated mutations remain obscure. We performed exome sequencing to determine the association of previously known mutations (driver gene mutations) with asbestos and to identify novel mutations related to asbestos exposure in lung adenocarcinoma (LAC) and MM. METHODS: Exome sequencing was performed on DNA from 47 tumor tissues of MM (21) and LAC (26) patients, 27 of whom had been asbestos-exposed (18 MM, 9 LAC). In addition, 9 normal lung/blood samples of LAC were sequenced. Novel mutations identified from exome data were validated by amplicon-based deep sequencing. Driver gene mutations in BRAF, EGFR, ERBB2, HRAS, KRAS, MET, NRAS, PIK3CA, STK11, and ephrin receptor genes (EPHA1-8, 10 and EPHB1-4, 6) were studied for both LAC and MM, and in BAP1, CUL1, CDKN2A, and NF2 for MM. RESULTS: In asbestos-exposed MM patients, previously non-described NF2 frameshift mutation (one) and BAP1 mutations (four) were detected. Exome data mining revealed some genes potentially associated with asbestos exposure, such as MRPL1 and SDK1. BAP1 and COPG1 mutations were seen exclusively in MM. Pathogenic KRAS mutations were common in LAC patients (42 %), both in non-exposed (n = 5) and exposed patients (n = 6). Pathogenic BRAF mutations were found in two LACs. CONCLUSION: BAP1 mutations occurred in asbestos-exposed MM. MRPL1, SDK1, SEMA5B, and INPP4A could possibly serve as candidate genes for alterations associated with asbestos exposure. KRAS mutations in LAC were not associated with asbestos exposure.

Genome-wide somatic mutation analysis of sinonasal adenocarcinoma with and without wood dust exposure.

BACKGROUND: Sinonasal adenocarcinoma is a rare cancer, encompassing two different entities, the intestinal-type sinonasal adenocarcinoma (ITAC) and the non-intestinal-type sinonasal adenocarcinoma (non-ITAC). Occurrence of ITAC is strongly associated with exposure to hardwood dusts. In countries with predominant exposure to softwood dust the occurrence of sinonasal adenocarcinomas is lower and the relative amount of non-ITACs to ITACs is higher. The molecular mechanisms behind the tumorigenic effects of wood dust remain largely unknown. METHODS: We carried out whole-genome sequencing of formalin-fixed paraffin-embedded (FFPE) samples of sinonasal adenocarcinomas from ten wood dust-exposed and six non-exposed individuals, with partial tobacco exposure data. Sequences were analyzed for the presence of mutational signatures matching COSMIC database signatures. Driver mutations and CN variant regions were characterized. RESULTS: Mutation burden was higher in samples of wood dust-exposed patients (p = 0.016). Reactive oxygen species (ROS) damage-related mutational signatures were almost exclusively identified in ITAC subtype samples (p = 0.00055). Tobacco smoke mutational signatures were observed in samples of patients with tobacco exposure or missing information, but not in samples from non-exposed patients. A tetraploidy copy number (CN) signature was enriched in ITAC subtype (p = 0.042). CN variation included recurrent gains in COSMIC Cancer Gene Census genes TERT, SDHA, RAC1, ETV1, PCM1, and MYC. Pathogenic variants were observed most frequently in TP53, NF1, CHD2, BRAF, APC, and LRP1B. Driver mutations and copy number gains did not segregate by subtype. CONCLUSIONS: Our analysis identified distinct mutational characteristics in ITAC and non-ITAC. Mutational signature analysis may eventually become useful for documentation of occupation-related cancer, while the exact mechanisms behind wood dust-driven carcinogenesis remain elusive. The presence of homologous recombination deficiency signatures implies a novel opportunity for treatment, but further studies are needed.

Similar DNA methylation pattern in lung tumours from smokers and never-smokers with second-hand tobacco smoke exposure.

Tobacco smoke causes lung cancer in smokers and in never-smokers exposed to second-hand tobacco smoke (SHS). Nonetheless, molecular mechanisms of lung cancer in SHS-exposed never-smokers are still elusive. We studied lung cancers from current smokers (n = 109), former smokers (n = 56) and never-smokers (n = 47) for promoter hypermethylation of five tumour suppressor genes--p16, RARB, RASSF1, MGMT and DAPK1--using methylation-specific polymerase chain reaction. Lung tumours from ever-smokers suggested an increased risk of p16 hypermethylation as compared to never-smokers (P = 0.073), with former smokers having the highest frequency of p16 hypermethylation (P = 0.044 versus current smokers and P = 0.009 versus never-smokers). In the never-smoking group, p16 hypermethylation was seen in lung tumours from SHS-exposed individuals (4/33; 12%) but in none of the non-exposed individuals (0/9). The overall occurrence of hypermethylation (measured both as methylation index and as number of genes affected) was similar in those ever exposed to tobacco smoke (smokers, SHS-exposed never-smokers) and differed from non-exposed never-smokers. In multivariate analysis, p16 hypermethylation was more prevalent in lung tumours from male than female patients (P = 0.018) and in squamous cell carcinomas than in adenocarcinomas (P = 0.025). Occurrence of TP53 mutation in the tumour was associated with hypermethylation of at least one gene (P = 0.027). In all, our data suggest that promoter hypermethylation pattern in SHS-exposed never-smokers resembles that observed in smokers. Association between TP53 mutation, a hallmark of smokers' lung cancer, and methylation of one or more of the lung cancer-related genes studied, provides further evidence for common tobacco smoke-related origin for both types of molecular alterations.

Occurrence of Sinonasal Intestinal-Type Adenocarcinoma and Non-Intestinal-Type Adenocarcinoma in Two Countries with Different Patterns of Wood Dust Exposure.

Sinonasal intestinal-type adenocarcinoma is strongly associated with hardwood dust exposure. Non-intestinal-type adenocarcinoma is a rarer and less well-known subtype considered not to be related with wood dust exposure. We determined the relative numbers of these two tumor types in 56 sinonasal adenocarcinoma patients in France and Finland, relating them with carefully assessed wood dust exposure histories. Diagnostic workup including immunohistochemistry for the intestinal markers CDX2 and CK20 indicated that the proportions of the two tumors differed significantly between France and Finland. In Finnish samples non-intestinal adenocarcinomas were more common than intestinal-type adenocarcinomas (12 non-intestinal vs. nine intestinal), while in the French samples the reverse was true (six non-intestinal vs. 29 intestinal). Such remarkably dissimilar occurrence of these tumors in France and Finland presumably reflects different pathogenetic circumstances in the two countries, and perhaps their different patterns of wood dust exposure. In France the main source of wood dust is from hardwoods. In Finland it is derived from softwoods. This is the first systematic comparison of the occurrence of intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma in two countries with different wood usage. It appears to be the first systematic study on differences in wood dust exposure between intestinal-type adenocarcinoma and non-intestinal-type adenocarcinoma.

Mutations in TP53 tumor suppressor gene in wood dust-related sinonasal cancer.

The causal role of work-related exposure to wood dust in the development of sinonasal cancer has long been established by numerous epidemiologic studies. To study molecular changes in these tumors, we analyzed TP53 gene mutations in 358 sinonasal cancer cases with or without occupational exposure to wood dust, using capillary electrophoresis single-strand conformation polymorphism analysis and direct sequencing. A significant association between wood-dust exposure and adenocarcinoma histology was observed [adjusted odds ratio (OR) 12.6, 95% confidence interval (CI), 5.0-31.6]. TP53 mutations occurred in all histologies, with an overall frequency of 77%. TP53 mutation positive status was most common in adenocarcinoma (OR 2.0, 95% CI, 1.1-3.7; compared with squamous cell carcinoma), and mutation positivity showed an overall, nonsignificant association with wood-dust exposure (OR 1.6, 95% CI, 0.8-3.1). Risk of TP53 mutation was significantly increased in association with duration (> or =24 years, OR 5.1, 95% CI, 1.5-17.1), average level (>2 mg/m(3); OR 3.6, 95% CI, 1.2-10.8) and cumulative level (> or =30 mg/m(3) x years; OR 3.5, 95% CI, 1.2-10.7) of wood-dust exposure; adjustment for formaldehyde affected the ORs only slightly. Smoking did not influence the occurrence of TP53 mutation; however, it was associated with multiple mutations (p = 0.03). As far as we are aware, this is the first study to demonstrate a high prevalence of TP53 mutation-positive cases in a large collection of sinonasal cancers with data on occupational exposure. Our results indicate that mutational mechanisms, in particular TP53 mutations, are associated with work-related exposure to wood dust in sinonasal cancer.

Profile of TP53 gene mutations in sinonasal cancer.

Genetic alterations underlying the development of the cancer of the nose and paranasal sinuses (sinonasal cancer, SNC), a rare cancer that can be included in the group of head and neck cancers, are still largely unknown. We recently reported that TP53 mutations are a common feature of SNC, with an overall frequency of 77%, and they show association to adenocarcinoma and wood-dust exposure [15]. In this study, we report in detail the sequence change for 159 TP53 mutations identified by direct sequencing. More than half of the mutations (60%, 95/159) were missense mutations; there were also 28 (18%) frameshift or nonsense mutations, and 36 (23%) intronic or silent mutations. In coding region, the most common base change detected was C-->T transition (43/125; 34% of base changes in the coding region). G-->T transversions occurred at a frequency of 10% (12/125), which is less than reported in mutation databases for head and neck squamous cell carcinoma (24%). Characteristically, in our SNC series, the mutations were scattered over a large number of codons, codon 248 being the most frequent target of base substitution. Codon 135 was the second most frequently mutated codon; this nucleotide position has not been reported before as frequently mutated in head and neck cancer or human cancer in general. About half of all tumours with TP53 mutations carried more than one mutation. Interestingly, 86% (19/22) of the silent mutations detected had occurred in tumours with multiple mutations.

Relationship between TP53 tumour suppressor gene mutations and smoking-related bulky DNA adducts in a lung cancer study population from Hungary.

Lung cancer rate in Hungary is one of the highest in the world among men and also very high among women, for reasons not clearly understood yet. The aim of the study was to explore characteristics of DNA damage and TP53 gene mutations in lung cancer from Hungary. Tissue samples from 104 lung resections for lung cancer patients, both men and women, operated on for non-small cell lung cancer, specifically, primary squamous cell carcinoma or adenocarcinoma were studied. Of the cases, 37% smoked up to the surgery, 24% stopped smoking within 1 year before the surgery, 26% stopped smoking more than a year before the surgery and 13% never smoked. TP53 mutations were detected by denaturant gradient gel electrophoresis, automated capillary electrophoresis single-strand conformation polymorphism and sequencing. Bulky DNA adduct levels were determined by (32)P-post-labelling in non-tumorous lung tissue. In total, 45% (47/104) of the cases carried TP53 mutation. The prevalence of TP53 mutations was statistically significantly associated with duration of smoking, tumour histology and gender. Smokers had approximately twice as high bulky adduct level as the combined group of former- and never-smokers (10.9 +/- 6.5 versus 5.5 +/- 3.4 adducts/10(8) nucleotides). The common base change G --> T transversion (8/43; 19%) was detected exclusively in smokers. For the first time, we demonstrate that most carriers of G --> T transversions had also a high level of bulky DNA adducts in their non-tumourous lung tissue. Our study provides evidence for a high burden of molecular alterations occurring concurrently in the lung of lung cancer patients.

Do individual and work-related factors differentiate work participation trajectories before and after vocational rehabilitation?

BACKGROUND: Understanding diverse labor market trajectories around vocational rehabilitation provides important insight into potential effectiveness of rehabilitation efforts. We examined factors associated with work participation trajectories before and after vocational rehabilitation. METHODS: Using nationwide Finnish register data of 7180 vocational rehabilitees, we constructed latent trajectory groups of work participation two years before and two years after their rehabilitation episode starting in 2008-2010. We plotted changes in labor market statuses in these groups and examined other associated factors using multinomial logistic regression. RESULTS: We identified four trajectories based on work participation levels before and after vocational rehabilitation. The "High-Resumed" group (35.6%) typically returned to full duties. The "High-to-Negligible" group (20.7%) typically transitioned to full disability retirement or unemployment. Among the "Medium-Resumed" (25.5%) and "Longstanding Negligible" (18.3%) groups, work disability and unemployment were common before rehabilitation, but afterwards those assigned to the former group often returned to full or partial duties. Overall, older age, male gender, living in areas with lower employment rates, having lower education, being employed in the private sector, and having mental diagnoses were associated with the other three trajectories than the most favorable "High-Resumed" trajectory. Furthermore, certain industrial sectors, job exposures, and less common diagnoses further separated specific trajectories. CONCLUSIONS: Work participation trajectories around vocational rehabilitation are diverse, only partly dependent on initial levels of work participation, and determined by various individual and work-related factors. Future nationwide studies should assess the effectiveness of vocational rehabilitation taking into consideration both individual and work-related factors.

The effectiveness of vocational rehabilitation on work participation: a propensity score matched analysis using nationwide register data.

Objective Research on the effectiveness of vocational rehabilitation has focused on small and selected groups, lacked proper controls, or not captured dynamic changes in work participation. Using rich nationwide data on vocational rehabilitees and matched controls, long-term changes in work participation before and after vocational rehabilitation were examined to assess its effectiveness. Methods Representative Finnish register data were used to examine 3199 recently employed individuals aged 30-55 years with histories of musculoskeletal- and mental-related work disability starting vocational rehabilitation in 2008-2010 (intervention group), and 3199 propensity score matched non-rehabilitees (control group). Sociodemographic and work-related factors and detailed 3-year work disability and other labor market history were used for matching. Generalized estimation equations were used to examine differences in the proportion of time spent at work between periods before and after rehabilitation among the intervention and control group and the difference in these differences (DID). Results Vocational rehabilitation resulted in gains in work participation, the total 1-, 2-, and 3-year DID being 11.8 [95% confidence interval (CI) 10.0-13.7], 8.9 (95% CI 7.6-10.2), and 7.2 (95% CI 6.1-8.3) percentage points, respectively. Contrary to this overall pattern, larger DID was observed over the long term for those whose rehabilitation lasted >10 months. The DID was lowest among women with musculoskeletal diseases. Conclusions Vocational rehabilitation after musculoskeletal- or mental-related work disability showed modest effectiveness on work participation. To promote sustained work participation after shorter rehabilitation (likely comprising workplace interventions) and faster work resumption after longer rehabilitation (likely comprising training), enhanced and complementary interventions should be considered.

Controlling for Structural Changes in the Workforce Influenced Occupational Class Differences in Disability Retirement Trends.

We explored occupational class differences in disability retirement trends accounting for structural changes in the workforce induced by the recent economic crisis and the following economic stagnation. Using nationwide register data on the general Finnish population aged 30-59 years, we examined trends in disability retirement due to all causes, musculoskeletal diseases, and mental disorders in 2007, 2010, and 2013. Applying propensity score (PS) matching to control for bias induced by structural changes in the workforce over time, we obtained 885,807 matched triplets. In the original study population, all-cause and cause-specific disability retirement declined between 2007 and 2013 for most occupational classes. In the matched study population, the disability retirement among skilled and unskilled manual workers sharply increased in 2010 and then declined in 2013. PS matching considerably attenuated the decline in disability retirement, particularly between the years 2007 and 2010. In general, the differences in disability retirement between both skilled and unskilled manual workers and upper-level non-manual employees widened during the period of economic stagnation. In occupational epidemiology, structural changes in the workforce should be accounted for when analysing trends in ill-health. Controlling for these changes revealed widening occupational class differences in disability retirement during the period of economic stagnation.

Early part-time sick leave results in considerable savings in social security costs at national level: an analysis based on a quasi-experiment in Finland.

Objectives We analyzed social security costs based on an earlier quasi-experiment that compared work participation between partial sickness beneficiaries and a matched group of full sickness beneficiaries. Methods Utilizing a population-based 70% representative sample, 1878 persons with part-time sick leave (intervention group) due to musculoskeletal diseases or mental disorders at an early stage of work disability and their propensity-score-matched controls with full-time sick leave were followed for two years. The outcome was the difference (absolute and relative) in social security costs between the intervention and control groups during follow-up. Costs of sickness absence, vocational rehabilitation, unemployment, and retirement days were calculated from national administrative registers. Results A cost reduction of €2395 per person per year [95% confidence interval (CI) -2890- -1899) was observed in the intervention compared with the control group. The cost ratio was 0.512 (95% CI 0.511-0.513). The largest savings were attributable to differences in the costs of retirement and vocational rehabilitation. The savings were higher for the second compared with the first follow-up year. Costs were saved across both genders and diagnostic groups, however, savings for women with musculoskeletal diseases were lowest. Conclusions Part-time instead of full-time sick leave, at the early stage of work disability due to musculoskeletal diseases or mental disorders, leads to considerable social security cost savings during two years, in correspondence with increased work participation and in addition to earlier reported health benefits. Part-time sick leave can be recommended from an economic perspective; however more consideration should be given to women with musculoskeletal diseases.

Risk Factors for Low Back Pain: A Population-Based Longitudinal Study.

OBJECTIVE: To identify risk factors for low back pain (LBP) and lumbar radicular pain and to assess whether obesity and exposure to workload factors modify the effect of leisure-time physical activity on LBP and lumbar radicular pain. METHODS: The population of this 11-year longitudinal study consists of a nationally representative sample of Finns ages ≥30 years (n = 3,505). The outcomes of the study were LBP and lumbar radicular pain for >7 days or for >30 days in the past 12 months at follow-up. RESULTS: LBP and lumbar radicular pain were more common in women than in men. LBP slightly declined with increasing age, while lumbar radicular pain increased with age. Abdominal obesity (defined by waist circumference) increased the risk of LBP (adjusted odds ratio [OR] 1.40 [95% confidence interval (95% CI) 1.16-1.68] for LBP >7 days and adjusted OR 1.41 [95% CI 1.13-1.76] for LBP >30 days) and general obesity (defined by body mass index) increased the risk of lumbar radicular pain (adjusted OR 1.44 [95% CI 1.12-1.85] for pain >7 days and adjusted OR 1.62 [95% CI 1.16-2.26] for pain >30 days). Smoking and strenuous physical work increased the risk of both LBP and lumbar radicular pain. Walking or cycling to work reduced the risk of LBP, particularly LBP for >30 days (adjusted OR 0.75 [95% CI 0.59-0.95]), with the largest reductions among nonabdominally obese individuals and among those not exposed to physical workload factors. Using vibrating tools increased the risk of lumbar radicular pain. CONCLUSION: Lifestyle and physical workload factors increase the risk of LBP and lumbar radicular pain. Walking and cycling may have preventive potential for LBP.

COX-2 and p53 in human sinonasal cancer: COX-2 expression is associated with adenocarcinoma histology and wood-dust exposure.

The causal role of wood-dust exposure in sinonasal cancer (SNC) has been established in epidemiological studies, but the mechanisms of SNC carcinogenesis are still largely unknown. Increased amounts of COX-2 are found in both premalignant and malignant tissues, and experimental evidence link COX-2 to development of cancer. Many signals that activate COX-2 also induce tumor suppressor p53, a transcription factor central in cellular stress response. We investigated COX-2 and p53 expressions by immunohistochemistry in 50 SNCs (23 adenocarcinomas, and 27 squamous cell carcinomas (SCC); 48 analyzed for COX-2; 41 for p53). Occupational histories and smoking habits were available for majority of the cases. Most of the adenocarcinoma cases with exposure history data had been exposed to wood dust at work in the past (88%, 14/16). For smokers, 63% (12/19) presented with SSC, whereas 64% (7/11) of nonsmokers displayed adenocarcinoma. COX-2 was expressed at higher levels in adenocarcinoma as compared to SSC (p < 0.001). COX-2 expression showed significant association with occupational exposure to wood dust (p = 0.024), and with nonsmoking status (p = 0.001). No statistically significant associations between the exposures and p53 accumulation were found; however, the p53 accumulation pattern (p = 0.062 for wood dust exposure) resembled that of COX-2 expression. In summary, our findings show increased COX-2 expression in SNC adenocarcinoma with wood dust exposure, suggesting a role for inflammatory components in the carcinogenesis process. In contrast, SCCs predominated among smokers and expressed COX-2 rarely; this may suggest at least partially different molecular mechanisms.

The association between obesity and the prevalence of low back pain in young adults: the Cardiovascular Risk in Young Finns Study.

Both low back pain (LBP) and obesity are common public health problems, yet their relation remains controversial. The aim of this study was to investigate the associations between weight-related factors and the prevalence of LBP in young adults in Finland. Participants in the ongoing Cardiovascular Risk in Young Finns Study aged 24-39 years were included (N = 2,575). In 2001, 31.2% of men and 39.5% of women reported LBP with recovery within a month or recurrent or continuous pain during the preceding 12 months. For women only, those with higher body mass index, waist circumference, hip circumference, waist-to-hip ratio, serum leptin level, and C-reactive protein level showed an increased prevalence of LBP. With all weight-related factors in the model, only waist circumference was related to LBP in women. For women, the odds ratios of LBP were 1.2 (95% confidence interval: 0.8, 1.8) for a waist circumference of 80-87.9 cm and 1.8 (95% confidence interval: 1.0, 3.2) for a waist circumference of > or =88 cm compared with a waist circumference of <80 cm. This association was independent of C-reactive protein, leptin, and adiponectin levels. The authors' findings in a relatively young population suggest that abdominal obesity may increase the risk of LBP in women.

Promoter hypermethylation in tumour suppressor genes shows association with stage, grade and invasiveness of bladder cancer.

AIMS: Superficial bladder cancer is a highly recurrent disease, with progression to muscle invasiveness occurring in 15-30% of cases. Promoter hypermethylation in a panel of tumour suppressor genes involved in cell cycle control, apoptosis and DNA repair was analyzed in superficial bladder tumours in order to evaluate the suitability of epigenetic biomarkers for an earlier prediction of the aggressive course of the disease. METHOD: Promoter hypermethylation in p16, RARbeta, RASSF1A, DAPK, and MGMT genes was analyzed in 58 cases with superficial bladder cancer and 2 cases with benign urological disease using methylation-specific PCR. RESULTS: Promoter hypermethylation was frequently detected in RARbeta, RASSF1A and DAPK genes, and 62% of bladder tumours exhibited hypermethylation in at least one gene. The overall frequency of hypermethylation and the number of genes involved increased with tumour stage, grade and muscle invasiveness. Aberrant methylation of RASSF1A and RARbetawas predominant (p < 0.05) in muscle-invasive tumours and high-grade tumours, respectively. Cases with concurrent hypermethylation in DAPK, p16 and RARbeta genes were moresusceptible to relapse. CONCLUSION: The results suggest analysis of promoter hypermethylation as a valuable biomarker for prognosis of the aggressive course of disease in bladder cancer.

K-ras mutations in sinonasal cancers in relation to wood dust exposure.

BACKGROUND: Cancer in the sinonasal tract is rare, but persons who have been occupationally exposed to wood dust have a substantially increased risk. It has been estimated that approximately 3.6 million workers are exposed to inhalable wood dust in EU. In previous small studies of this cancer, ras mutations were suggested to be related to wood dust exposure, but these studies were too limited to detect statistically significant associations. METHODS: We examined 174 cases of sinonasal cancer diagnosed in Denmark in the period from 1991 to 2001. To ensure uniformity, all histological diagnoses were carefully reviewed pathologically before inclusion. Paraffin embedded tumour samples from 58 adenocarcinomas, 109 squamous cell carcinomas and 7 other carcinomas were analysed for K-ras codon 12, 13 and 61 point mutations by restriction fragment length polymorphisms and direct sequencing. Information on occupational exposure to wood dust and to potential confounders was obtained from telephone interviews and from registry data. RESULTS: Among the patients in this study, exposure to wood dust was associated with a 21-fold increased risk of having an adenocarcinoma than a squamous cell carcinoma compared to unexposed [OR = 21.0, CI = 8.0-55.0]. K-ras was mutated in 13% of the adenocarcinomas (seven patients) and in 1% of squamous cell carcinomas (one patient). Of these eight mutations, five mutations were located in the codon 12. The exact sequence change of remaining three could not be identified unambiguously. Among the five identified mutations, the G-->A transition was the most common, and it was present in tumour tissue from two wood dust exposed adenocarcinoma patients and one patient with unknown exposure. Previously published studies of sinonasal cancer also identify the GGT --> GAT transition as the most common and often related to wood dust exposure. CONCLUSION: Patients exposed to wood dust seemed more likely to develop adenocarcinoma compared to squamous cell carcinomas. K-ras mutations were detected in 13% of adenocarcinomas. In this study and previously published studies of sinonasal cancer the found K-ras mutations, were almost exclusively G --> A transitions. In conclusion, our study, based on a large representative collection of human SNC tumours, indicates that K-ras mutations are relatively infrequent, and most commonly occur in adenocarcinomas. Wood dust exposure alone was not found to be explanatory for the G-->A mutations, but combination of exposure to tobacco, wood dust, and possibly other occupational agents may be a more likely explanation. Overall, the study suggests a limited role for K-ras mutations in development of sinonasal cancer.

Asthma incidence in wood-processing industries in Finland in a register-based population study.

OBJECTIVES: This register-based population study determined incidence rates of clinically verified asthma among woodworkers, other blue-collar workers, and administrative personnel employed in wood-processing industries in Finland. Exposure to wood dust was under special scrutiny. METHODS: All Finns employed in wood-processing industries were followed for asthma incidence via record linkage in the years 1986-1998. Incident cases included people with asthma reimbursed for medication by the national health insurance or registered as having occupational asthma. Age-adjusted incidence rates and relative risks (RR) by gender were estimated for wood workers, other blue-collar workers, and administrative employees (referents) in wood industries. RESULTS: The relative risk of asthma was increased for all woodworkers among both genders [men: RR 1.5, 95% confidence interval (95% CI) 1.2-1.8; women: RR 1.5, 95% Cl 1.2-1.7]; a similarly elevated risk was also found for other blue-collar workers (men: RR 1.5, 95% Cl 1.2-1.8; women: RR 1.4, 95% Cl 1.2-1.6) in the same wood industries. Statistically increased relative risks were found for low and medium exposure to wood dust, but not for high exposure. Altogether 217 of the 4074 clinically verified asthma cases were reported as occupational asthma in the Finnish Register on Occupational Diseases. CONCLUSIONS: The incidence rates for asthma were significantly increased both among the woodworkers and the other blue-collar workers in wood industries but without a clear dose-response. Cases recognized as occupational asthma accounted for only a small part of the total asthma excess, indicating that much of the work-related asthma excess remains unrecognized in these industries.