Franco Merletti

A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 × 10-10). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 × 10-20 overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N′-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

Meta-analysis of non-sentinel node metastases associated with micrometastatic sentinel nodes in breast cancer.

The need for further axillary treatment in patients with breast cancer with low‐volume sentinel node (SN) involvement (micrometastases or smaller) is controversial.

Risk of oral squamous cell carcinoma in 402 patients with oral lichen planus: a follow-up study in an Italian population

The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis.

Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies

Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age‐adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8–143.2) for SqCC, 111.3 (95% CI: 69.8–177.5) for SCLC and 21.9 (95% CI: 16.6–29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5–124.6), 108.6 (95% CI: 50.7–232.8) and 16.8 (95% CI: 9.2–30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

Lung cancer and cigarette smoking in Europe: An update of risk estimates and an assessment of inter-country heterogeneity

Ten case‐control studies have been carried out in 6 European countries to investigate the major risk factors for lung cancer. Carcinogenic effect from cigarette smoke was the most relevant interest in our study, which has included 7,609 cases of lung cancer and 10,431 controls, mainly population based. The results indicate elevated odds ratios (ORs; 23.9 among men and 8.7 among women) with attributable risks exceeding 90% for men and close to 60% for women. A large, and statistically significant, variability of the results across countries was detected after adjusting for the most common confounding variables, and after controlling, at least in part, for the instability of the ORs due to the small number of non‐smokers in some of the study subsets. This pattern of lung cancer risk associated with cigarettes smoke, across different European regions, reflects inherent characteristics of the studies as well as differences in smoking habits, particularly calender periods of starting, and it is likely to have been influenced by effect modifiers like indoor radon exposure, occupation, air pollution and dietary habits.

Multiple ADH genes are associated with upper aerodigestive cancers

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10−10 and 10−9, respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: A pooled analysis of two large studies

The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case‐control studies was used. Subjects included 1,263 never smoking lung cancer patients and 2,740 population and hospital controls recruited during 1985–1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01–1.37) and for long‐term exposure was 1.23 (95% CI = 1.01–1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99–1.36) and for long‐term exposure was 1.27 (95% CI = 1.03–1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A dose‐response relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10–1.79) for the long‐term exposure from all sources. There was no evidence of confounding by employment in high‐risk occupations, education or low vegetable intake. Sensitivity analysis for the effects of misclassification (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear dose‐response relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the development of lung cancer among never smokers.

Mortality among workers employed in the titanium dioxide production industry in Europe

AbstractObjectives: To assess the risk of lung cancer mortality related to occupational exposure to titanium dioxide (TiO2). Methods: A mortality follow-up study of 15,017 workers (14,331 men) employed in 11 factories producing TiO2 in Europe. Exposure to TiO2 dust was reconstructed for each occupational title; exposure estimates were linked with the occupational history. Observed mortality was compared with national rates, and internal comparisons were based on multivariate Cox regression analysis. Results: The cohort contributed 371,067 person-years of observation (3.3% were lost to follow-up and 0.7% emigrated). 2652 cohort members died during the follow-up, yielding standardized mortality ratios (SMRs) of 0.87 (95% confidence interval [CI] 0.83–0.90) among men and 0.58 (95% CI 0.40–0.82) among women. Among men, the SMR of lung cancer was significantly increased (1.23, 95% CI 1.10–1.38); however, mortality from lung cancer did not increase with duration of employment or estimated cumulative exposure to TiO2 dust. Data on smoking were available for over one third of cohort members. In three countries, the prevalence of smokers was higher among cohort members compared to the national populations. Conclusions: The results of the study do not suggest a carcinogenic effect of TiO2 dust on the human lung.

Continuous positive airway pressure for treatment of respiratory complications after abdominal surgery: a systematic review and meta-analysis

Objective:We evaluated the potential benefit of continuous positive airway pressure (CPAP) to prevent postoperative pulmonary complications (PPCs), atelectasis, pneumonia, and intubation in patients undergoing major abdominal surgery. Summary Background Data:PPCs are common during the postoperative period and may be associated with a high morbidity rate. Efficacy of CPAP to prevent PPCs occurrence is controversial. Methods:Medical literature databases were searched for randomized controlled trials examining the use of CPAP versus standard therapy in patients undergoing abdominal surgery. The meta-analysis estimated the pooled risk ratio and the number needed to treat to benefit (NNTB) for PPCs, atelectasis, and pneumonia. Results:The meta-analysis was carried out over 9 randomized controlled trials. Overall, CPAP significantly reduced the risk of (1) PPCs (risk ratio, 0.66; 95% confidence interval [CI], 0.52–0.85) with a corresponding NNTB of 14.2 (95% CI, 9.9–32.4); (2) atelectasis (risk ratio, 0.75; 95% CI, 0.58–0.97; NNTB, 7.3; 95% CI, 4.4–64.5); (3) pneumonia (risk ratio, 0.33; 95% CI, 0.14–0.75; NNTB, 18.3; 95% CI, 14.4–48.8). In all cases the variation in risk ratio attributable to heterogeneity was negligible, although there was some evidence of publication bias. Conclusions:This systematic review suggests that CPAP decreases the risk of PPCs, atelectasis, and pneumonia and supports its clinical use in patients undergoing abdominal surgery.

Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals

BACKGROUND Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. METHODS We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. RESULTS Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour. CONCLUSIONS This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.