Lorenzo Simonato

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.

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.

Food groups and risk of squamous cell esophageal cancer in Northern Italy

To better understand the nutritional etiology of squamous cell esophageal cancer, we conducted a case‐control study in 3 areas of northern Italy. A total of 304 incident, histologically confirmed cases of squamous cell carcinoma of the esophagus (275 men, 29 women) and 743 hospital controls (593 men, 150 women) with acute, non‐neoplastic conditions, not related to smoking, alcohol consumption or long‐term diet modification, were interviewed during 1992 to 1997. The validated food‐frequency questionnaire included 78 questions on food items or recipes, which were then categorized into 19 main food groups, and 10 questions on fat intake pattern. After allowance for age, sex, education, area of residence, tobacco smoking, alcohol drinking and non‐alcohol energy, a significant increased risk emerged for high consumption of soups (OR=2.1 for the highest vs. lowest quintile), whereas inverse associations with esophageal cancer risk were observed for pasta and rice (OR=0.7), poultry (OR=0.4), raw vegetables (OR=0.3), citrus fruit (OR=0.4) and other fruit (OR=0.5). The associations with dietary habits were consistent in different strata of tobacco smoking and alcohol drinking. Among added lipids, olive oil intake showed a significant reduction of esophageal cancer risk, even after allowance for total vegetable consumption (OR=0.4), while butter consumption was directly associated with this risk (OR=2.2). Our results thus provide further support to the evidence that raw vegetables and citrus fruit are inversely related to the risk of squamous cell esophageal cancer and suggest that olive oil may also reduce this risk. Int. J. Cancer 87:289–294, 2000.

Risk of cancer other than Kaposi's sarcoma and non-Hodgkin's lymphoma in persons with AIDS in Italy

Record linkage was carried out between the national Registry of AIDS and 13 Cancer Registries (CRs) covering, in 1991, about 15% of the Italian population. Observed and expected numbers of cancers and standardized incidence ratios (SIRs) were assessed in 6067 persons with AIDS, for a total of 25,759 person-years. Significantly increased SIRs were found for Hodgkins disease [8.9, 95% confidence interval (CI) 4.4-16.0], in which seven of 11 cases were of mixed cellularity type; invasive carcinoma of the cervix uteri (15.5; 95% CI 4.0-40.1); and non-melanomatous skin cancer (3.0, 95% CI 1.3-5.9), in which five of eight cases were basal cell carcinoma. An excess was also seen for brain tumours, but this may be partly due to misdiagnosis of brain non-Hodgkins lymphoma or other brain diseases occurring near the time of the AIDS diagnosis. The risk for all cancer types, after exclusion of Kaposis sarcoma (KS) and non-Hodgkins lymphoma (NHL), was approximately twice the general population risk. An increased SIR for Hodgkins disease in persons with AIDS is thus confirmed, though it is many times smaller than that for NHL. An association with invasive carcinoma of the cervix is also shown at a population level. The excess of non-melanomatous skin cancer seems to be lower than in transplant recipients.

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.

Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in northern Italy

Between 1992 and 1997, we conducted a case‐control study of oesophageal cancer in 3 areas of northern Italy. Cases were 275 men, ages 39–77 years (median age 60), with a first incident squamous‐cell carcinoma of the oesophagus. Controls were 593 men, ages 36–77 years (median age 60) admitted for acute illnesses, unrelated to tobacco and alcohol, to major hospitals of the areas under surveillance. Number of daily cigarettes was strongly associated with risk [odds ratio (OR) for ≥25 cigarettes/day = 7.0)]. Long‐duration smoking showed particularly elevated ORs (OR = 6.4 for ≥35 years), and excess risk declined after smoking cessation (OR = 1.5 after ≥10 years). Oesophageal cancer risk steeply rose with increasing level of alcohol consumption. ORs were 6.2 for 35–55 drinks and 24.5 for 84 drinks or more per week. No trend in risk emerged for duration of alcohol drinking or age at start of drinking. The risk in the highest joint level of alcohol drinking and current smoking was increased 130 folds (i.e., compatible with a multiplicative model). Excess risk in drinkers chiefly derived from wine. In conclusion, alcohol drinking and cigarette smoking were both important, but the roles of dose and duration of exposure differed. The association with alcohol was stronger than the one with smoking by exposure intensity, but apparently unaffected by duration or other temporal variables. Int. J. Cancer 86:144–149, 2000.

Gender differences in lung cancer risk by smoking: a multicentre case-control study in Germany and Italy.

Several studies in the past have shown appreciably higher lung cancer risk estimates associated with smoking exposure among men than among women, while more recent studies in the USA report just the opposite. To evaluate this topic in a European population we conducted a case–control study of lung cancer in three German and three Italian centres. Personal interviews and standardized questionnaires were used to obtain detailed life-long smoking and occupational histories from 3723 male and 900 female cases and 4075 male and 1094 female controls. Lung cancer risk comparing ever-smokers with never-smokers was higher among men (odds ratios (OR) adjusted for age and centre = 16.1, 95% confidence interval (CI) 12.8–20.3) than among women (OR = 4.2, CI 3.5–5.1). Because the smoking habits of women were different from men, we conducted more detailed analyses using comparable levels of smoking exposure. After restriction to smokers and adjustment for other smoking variables, risk estimates did not differ appreciably between genders. The analysis of duration of smoking (0–19, 20–39, 40+ years) adjusted for cigarette consumption and time since quitting smoking revealed similar risk estimates in men (OR = 1.0, 3.3 [CI 2.6–4.2], 4.1 [CI 3.1–5.6]) and women (OR = 1.0, 2.7 [CI 1.7–4.1], 3.3 [CI 1.9–5.8]). The same was true of the analysis of average or cumulative smoking consumption, and also of analyses stratified by different histological types. We conclude that for comparable exposure to tobacco smoke, the risk of lung cancer is comparable in women and men.

A historical prospective study of European stainless steel, mild steel, and shipyard welders.

A multicentre cohort of 11,092 male welders from 135 companies located in nine European countries has been assembled with the aim of investigating the relation of potential cancer risk, lung cancer in particular, with occupational exposure. The observation period and the criteria for inclusion of welders varied from country to country. Follow up was successful for 96.9% of the cohort and observed numbers of deaths (and for some countries incident cancer cases) were compared with expected numbers calculated from national reference rates. Mortality and cancer incidence ratios were analysed by cause category, time since first exposure, duration of employment, and estimated cumulative dose to total fumes, chromium (Cr), Cr VI, and nickel (Ni). Overall a statistically significant excess was reported for mortality from lung cancer (116 observed v 86.81 expected deaths, SMR = 134). When analysed by type of welding an increasing pattern with time since first exposure was present for both mild steel and stainless steel welders, which was more noticeable for the subcohort of predominantly stainless steel welders. No clear relation was apparent between mortality from lung cancer and duration of exposure to or estimated cumulative dose of Ni or Cr. Whereas the patterns of lung cancer mortality in these results suggest that the risk of lung cancer is higher for stainless steel than mild steel welders the different level of risk for these two categories of welding exposure cannot be quantified with precision. The report of five deaths from pleural mesothelioma unrelated to the type of welding draws attention to the risk of exposure to asbestos in welding activities.