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.

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.

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.

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.

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.

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.

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.

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.

Cause-specific sickness absence trends by occupational class and industrial sector in the context of recent labour market changes: a Finnish panel data study.

OBJECTIVES: We aimed to provide previously unestablished information on population-based differences in cause-specific sickness absence trends between occupational classes and further between four large industrial sectors within the different occupational classes while controlling for other socioeconomic factors and employment patterns. We focused on the period 2005-2013, during which the labour market underwent large economic and structural changes in many countries. DESIGN: Register-based panel data study. SETTING: Large representative datasets on Finnish wage earners aged 25-59 years. OUTCOME MEASURE: Annual risk of sickness absence (>10 working days) based on repeated logistic regression. RESULTS: Between 2005 and 2013, the proportion of employees with sickness absence decreased. Occupational class differences in sickness absence trends varied by disease group. Overall, the decrease in absences was smallest among lower non-manual employees. Sickness absence levels were highest in the health and social work sector and in the manufacturing sector within the non-manual and manual classes, respectively. Absences due to musculoskeletal diseases decreased temporarily during the peak of the economic recession in 2009, particularly in the manufacturing sector within the manual class. The decrease in absences due to musculoskeletal diseases was smallest in the trade sector within the lower occupational classes. Overall, education, income and employment patterns partly explained the differences in the absence levels, but not in the trends. CONCLUSIONS: We found a complex interplay between the associations of occupational class and industrial sector with sickness absence trends. During the economic recession, absences due to musculoskeletal diseases decreased temporarily in a segment of wage earners who were known to have been hit hard by the recession. However, the trend differences were not explained by the measured structural changes in the characteristics of the study population. Both occupational class and industrial sector should be taken into account when tackling problems of work disability.

Computed tomography in the evaluation of malignant pleural mesothelioma-Association of tumor size to a sarcomatoid histology, a more advanced TNM stage and poor survival.

OBJECTIVES: Appropriate clinical staging of malignant pleural mesothelioma (MPM) is critical for correct treatment decisions. Newly revised TNM staging protocol has been released for MPM. We investigated baseline computed tomography (CT) characteristics of MPM patients, the new staging system and a simple tumor size (TS) assessment in terms of survival. MATERIALS AND METHODS: As part of our study that included all MPM patients diagnosed in Finland 2000-2012, we retrospectively reviewed 161 CT scans of MPM patients diagnosed between 2007 and 2012 in the Hospital District of Helsinki and Uusimaa. TS was estimated by using the maximal tumor thickness and grading tumor extension along the chest wall. Cox Regression models were used to identify relationships between survival, clinicopathological factors and CT-findings. RESULTS: The median length of follow-up was 9.7 months and the median survival 9.1 months. The right sided tumors tended to be more advanced at baseline and had worse prognosis in the univariate analyses. In the multivariate survival model, TS, pleural effusion along with non-epithelioid histology were predictors of poor survival. Tumor size correlated significantly with a sarcomatoid histopathological finding and several parameters linked to a more advanced TNM stage. Most patients were diagnosed with locally advanced stage, while 12 (7%) had no sign of the tumor in CT. CONCLUSION: In this study, we demonstrate a novel approach for MPM tumor size evaluation that has a strong relationship with mortality, sarcomatoid histology and TNM stage groups. TS could be used for prognostic purposes and it may be a useful method for assessing therapy responses.

Labour Market Segregation and Gender Differences in Sickness Absence: Trends in 2005-2013 in Finland.

Objectives: Women have higher sickness absence rate than men, but less is known of changes in this difference over time. We examined gender differences in sickness absence trends focusing on gender segregation in the labour market. Methods: We used large nationwide register data on Finnish wage earners aged 25-59 and generalized estimation equations based on repeated logistic regression to estimate the annual risk of sickness absence lasting at least 2 weeks. Results: Between 2005 and 2013, the age-adjusted proportion (%) of employees with all-cause sickness absence decreased from the initial levels of 10.6 among men and 15.1 among women by 16.7 and 13.6%, respectively. Among both genders, the largest decrease in sickness absence coincided with the peak of the economic recession in 2009. In sickness absence due to all causes and musculoskeletal diseases, also the excess decrease among men mainly occurred in 2009, and in sickness absence due to mental disorders 2 years later. In sickness absence due to all causes and musculoskeletal diseases, the increasing gender difference was mainly attributable to a larger decrease in sickness absence at the time of the recession in male-dominated groups, such as in manual and manufacturing work, than in other sectors and occupational classes. In mental disorders, the increasing gender difference was partly attributable to a later smaller decrease in sickness absence among female-dominated lower non-manual and lower income employment groups. The increasing gender differences did not result from differential distributional changes in employment or sociodemographic factors among the employed male and female populations. In fact, widening of the gender gap in sickness absence due to all causes and musculoskeletal diseases would have been even larger without faster increase among women in the educational level and in non-manual employment. Conclusions: Sickness absence decreased especially in male-dominated employment groups, resulting in a larger decrease in absences among men compared with women. More research is needed to ascertain whether these differential changes are attributable, for example, to reduced willingness to seek medical advice or increased presenteeism in male-dominated groups, or to increased work pressures in female-dominated groups. Selection mechanisms, i.e. men's increased ill-health-related exit from work through other routes than sickness absence, also cannot be ruled out.

Legislative change enabling use of early part-time sick leave enhanced return to work and work participation in Finland.

Objectives The aim of the study was to assess the effectiveness of the use of part-time sick leave at the early (first 12 weeks) stage of work disability due to mental disorder or musculoskeletal disease on sustained return to work (RTW) and overall work participation. Methods In a nation-wide register-based quasi-experimental study, we compared sustained RTW (ie, ≥28 consecutive days at work) and 2-year work participation between the part- and full-time sickness absence (SA) benefit groups (N=1878 in each group) using propensity-score matching. Persons who received partial or full SA benefit due to musculoskeletal diseases or mental disorders between January 1, 2010 and December 31, 2011 were eligible as cases or controls, respectively. Results A higher proportion showed sustained RTW after part- compared to full-time sick leave [absolute risk difference 8.0%, 95% confidence interval (95% CI) 5.3-10.9]. Moreover, the proportion of time at work was at a 10.5% higher level in the part- compared to full-time sick leave group. The prevalence of full disability retirement was almost three-fold among the full- compared to part-time sick leave group, whereas partial disability retirement was 4.5-fold more prevalent in the part- compared to full-time sick leave group. Conclusions The use of part-time sick leave during the first three months of SA enhances RTW and overall work participation during two years among persons with mental disorders and musculoskeletal diseases. The prescription of part-time sick leave can be recommended at an early stage of work disability.

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.

Lifestyle Risk Factors Increase the Risk of Hospitalization for Sciatica: Findings of Four Prospective Cohort Studies.

BACKGROUND: The purpose of this study is to assess the effects of lifestyle risk factors on the risk of hospitalization for sciatica and to determine whether overweight or obesity modifies the effect of leisure-time physical activity on hospitalization for sciatica. METHODS: We included 4 Finnish prospective cohort studies (Health 2000 Survey, Mobile Clinic Survey, Helsinki Health Study, and Young Finns Study) consisting of 34,589 participants and 1259 hospitalizations for sciatica during 12 to 30 years of follow-up. Sciatica was based on hospital discharge register data. We conducted a random-effects individual participant data meta-analysis. RESULTS: After adjustment for confounding factors, current smoking at baseline increased the risk of subsequent hospitalization for sciatica by 33% (95% confidence interval [CI], 13%-56%), whereas past smokers were no longer at increased risk. Obesity defined by body mass index increased the risk of hospitalization for sciatica by 36% (95% CI 7%-74%), and abdominal obesity defined by waist circumference increased the risk by 41% (95% CI 3%-93%). Walking or cycling to work reduced the risk of hospitalization for sciatica by 33% (95% CI 4%-53%), and the effect was independent of body weight and other leisure activities, while other types of leisure activities did not have a statistically significant effect. CONCLUSIONS: Smoking and obesity increase the risk of hospitalization for sciatica, whereas walking or cycling to work protects against hospitalization for sciatica. Walking and cycling can be recommended for the prevention of sciatica in the general population.

Genome-Wide Meta-Analysis of Sciatica in Finnish Population.

Sciatica or the sciatic syndrome is a common and often disabling low back disorder in the working-age population. It has a relatively high heritability but poorly understood molecular mechanisms. The Finnish population is a genetic isolate where small founder population and bottleneck events have led to enrichment of certain rare and low frequency variants. We performed here the first genome-wide association (GWAS) and meta-analysis of sciatica. The meta-analysis was conducted across two GWAS covering 291 Finnish sciatica cases and 3671 controls genotyped and imputed at 7.7 million autosomal variants. The most promising loci (p<1x10-6) were replicated in 776 Finnish sciatica patients and 18,489 controls. We identified five intragenic variants, with relatively low frequencies, at two novel loci associated with sciatica at genome-wide significance. These included chr9:14344410:I (rs71321981) at 9p22.3 (NFIB gene; p = 1.30x10-8, MAF = 0.08) and four variants at 15q21.2: rs145901849, rs80035109, rs190200374 and rs117458827 (MYO5A; p = 1.34x10-8, MAF = 0.06; p = 2.32x10-8, MAF = 0.07; p = 3.85x10-8, MAF = 0.06; p = 4.78x10-8, MAF = 0.07, respectively). The most significant association in the meta-analysis, a single base insertion rs71321981 within the regulatory region of the transcription factor NFIB, replicated in an independent Finnish population sample (p = 0.04). Despite identifying 15q21.2 as a promising locus, we were not able to replicate it. It was differentiated; the lead variants within 15q21.2 were more frequent in Finland (6-7%) than in other European populations (1-2%). Imputation accuracies of the three significantly associated variants (chr9:14344410:I, rs190200374, and rs80035109) were validated by genotyping. In summary, our results suggest a novel locus, 9p22.3 (NFIB), which may be involved in susceptibility to sciatica. In addition, another locus, 15q21.2, emerged as a promising one, but failed to replicate.

Hot spot mutations in Finnish non-small cell lung cancers.

OBJECTIVES: Non-small cell lung cancer (NSCLC) is a common cancer with a poor prognosis. The aim of this study was to screen Finnish NSCLC tumor samples for common cancer-related mutations by targeted next generation sequencing and to determine their concurrences and associations with clinical features. MATERIALS AND METHODS: Sequencing libraries were prepared from DNA isolated from formalin-fixed, paraffin-embedded tumor material of 425 patients using the AmpliSeq Colon and Lung panel covering mutational hot spot regions of 22 cancer genes. Sequencing was performed with the Ion Torrent Personal Genome Machine (PGM). RESULTS: Data analysis of the hot spot mutations revealed mutations in 77% of the patients, with 7% having 3 or more mutations reported in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Two of the most frequently mutated genes were TP53 (46%) and KRAS (25%). KRAS codon 12 mutations were the most recurrently occurring mutations. EGFR mutations were significantly associated with adenocarcinoma, female gender and never/light-smoking history; CTNNB1 mutations with light ex-smokers, PIK3CA and TP53 mutations with squamous cell carcinoma, and KRAS with adenocarcinoma. TP53 mutations were most prevalent in current smokers and ERBB2, ERBB4, PIK3CA, NRAS, NOTCH1, FBWX7, PTEN and STK11 mutations occurred exclusively in a group of ever-smokers, however the association was not statistically significant. No mutation was found that associated with asbestos exposure. CONCLUSION: Finnish NSCLC patients have a similar mutation profile as other Western patients, however with a higher frequency of BRAF mutations but a lower frequency of STK11 and ERBB2 mutations. Moreover, TP53 mutations occurred frequently with other gene mutations, most commonly with KRAS, MET, EGFR and PIK3CA mutations.

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.

Evaluation of the validity of job exposure matrix for psychosocial factors at work.

OBJECTIVE: To study the performance of a developed job exposure matrix (JEM) for the assessment of psychosocial factors at work in terms of accuracy, possible misclassification bias and predictive ability to detect known associations with depression and low back pain (LBP). MATERIALS AND METHODS: We utilized two large population surveys (the Health 2000 Study and the Finnish Work and Health Surveys), one to construct the JEM and another to test matrix performance. In the first study, information on job demands, job control, monotonous work and social support at work was collected via face-to-face interviews. Job strain was operationalized based on job demands and job control using quadrant approach. In the second study, the sensitivity and specificity were estimated applying a Bayesian approach. The magnitude of misclassification error was examined by calculating the biased odds ratios as a function of the sensitivity and specificity of the JEM and fixed true prevalence and odds ratios. Finally, we adjusted for misclassification error the observed associations between JEM measures and selected health outcomes. RESULTS: The matrix showed a good accuracy for job control and job strain, while its performance for other exposures was relatively low. Without correction for exposure misclassification, the JEM was able to detect the association between job strain and depression in men and between monotonous work and LBP in both genders. CONCLUSIONS: Our results suggest that JEM more accurately identifies occupations with low control and high strain than those with high demands or low social support. Overall, the present JEM is a useful source of job-level psychosocial exposures in epidemiological studies lacking individual-level exposure information. Furthermore, we showed the applicability of a Bayesian approach in the evaluation of the performance of the JEM in a situation where, in practice, no gold standard of exposure assessment exists.

The role of obesity and physical activity in non-specific and radiating low back pain: the Young Finns study.

OBJECTIVE: To study the effects of obesity, physical activity, and change in physical activity on the incidence of low back pain and explore whether obesity modifies the effects of physical activity. METHODS: As part of the ongoing Young Finns Study, 1224 subjects aged 24-39 years free from low back pain during the preceding 12 months at baseline in 2001 were included. Obesity was defined based on the body mass index (BMI) and waist circumference, and physical activity was assessed by the metabolic equivalent of task (MET) index in 2001 and 2007. RESULTS: Abdominal obesity, defined by an increased waist circumference, was associated with an increased incidence of radiating low back pain (adjusted odds ratio (OR) = 1.7 and 95% confidence interval (CI) 1.1-2.7), while it had no effect on non-specific low back pain. BMI was associated neither with the incidence of radiating low back pain nor with non-specific low back pain. Compared with subjects who stayed active during follow-up, those with a low level of physical activity (adjusted OR = 2.0 and 95% CI 1.1-3.5) and active subjects who further increased their physical activity during follow-up (OR = 3.1 and 95% CI 1.5-6.7) had a higher incidence of radiating low back pain. Low level of physical activity was associated with an increased incidence of radiating low back pain in obese (OR = 3.3 and 95% 1.1-10.4), but not in non-overweight subjects (OR = 1.1 and 95% CI 0.6-1.9). Physical activity was not associated with non-specific low back pain. CONCLUSIONS: Our findings indicate that both obesity and low level of physical activity are independent risk factors of radiating low back pain. The current findings propose a U-shaped relation between physical activity and radiating low back pain. Moderate level of physical activity is recommended for the prevention of low back pain, especially in obese individuals. In all, our findings imply that obese individuals should stay physically active, even if they may not lose weight.