Genetic mutations associated with cigarette smoking in pancreatic cancer.
ABSTRACT: Cigarette smoking doubles the risk of pancreatic cancer, and smoking accounts for 20% to 25% of pancreatic cancers. The recent sequencing of the pancreatic cancer genome provides an unprecedented opportunity to identify mutational patterns associated with smoking. We previously sequenced >750 million bp DNA from 23,219 transcripts in 24 adenocarcinomas of the pancreas (discovery screen). In this previous study, the 39 genes that were mutated more than once in the discovery screen were sequenced in an additional 90 adenocarcinomas of the pancreas (validation screen). Here, we compared the somatic mutations in the cancers obtained from individuals who ever smoked cigarettes (n = 64) to the somatic mutations in the cancers obtained from individuals who never smoked cigarettes (n = 50). When adjusted for age and gender, analyses of the discovery screen revealed significantly more nonsynonymous mutations in the carcinomas obtained from ever smokers (mean, 53.1 mutations per tumor; SD, 27.9) than in the carcinomas obtained from never smokers (mean, 38.5; SD, 11.1; P = 0.04). The difference between smokers and nonsmokers was not driven by mutations in known driver genes in pancreatic cancer (KRAS, TP53, CDKN2A/p16, and SMAD4), but instead was predominantly observed in genes mutated at lower frequency. No differences were observed in mutations in carcinomas from the head versus tail of the gland. Pancreatic carcinomas from cigarette smokers harbor more mutations than do carcinomas from never smokers. The types and patterns of these mutations provide insight into the mechanisms by which cigarette smoking causes pancreatic cancer.
Project description:BACKGROUND:TP53 mutations are among the most common mutations found in lung cancers, identified as an independent prognostic factor in many types of cancers. The purpose of this study was to investigate the frequency and prognostic impact of TP53 mutations in never-smokers and in different histological subtypes of lung cancer. METHODS:We analyzed tumor tissue from 394 non-small cell carcinomas including adenocarcinomas (n = 229), squamous cell carcinomas (n = 112), large cell carcinomas (n = 30), and others (n = 23) for mutations in TP53 by the use of Sanger sequencing (n = 394) and next generation sequencing (n = 100). RESULTS:TP53 mutations were identified in 47.2% of the samples, with the highest frequency (65%) of mutations among squamous cell carcinomas. Among never-smokers, 36% carried a TP53 mutation, identified as a significant independent negative prognostic factor in this subgroup. For large cell carcinomas, a significantly prolonged progression free survival was found for those carrying a TP53 mutation. In addition, the frequency of frameshift mutations was doubled in squamous cell carcinomas (20.3%) compared to adenocarcinomas (9.1%). CONCLUSION:TP53 mutation patterns differ between the histological subgroups of lung cancers, and are also influenced by smoking history. This indicates that the histological subtypes in lung cancer are genetically different, and that smoking-induced TP53 mutations may have a different biological impact than TP53 mutations occurring in never-smokers.
Project description:Many adolescents and young adults use alternative tobacco products, such as water pipes and snus, instead of cigarettes.To assess whether prior water pipe tobacco smoking and snus use among never smokers are risk factors for subsequent cigarette smoking.We conducted a 2-wave national longitudinal study in the United States among 2541 individuals aged 15 to 23 years old. At baseline (October 25, 2010, through June 11, 2011), we ascertained whether respondents had smoked cigarettes, smoked water pipe tobacco, or used snus. At the 2-year follow-up (October 27, 2012, through March 31, 2013), we determined whether baseline non-cigarette smokers had subsequently tried cigarette smoking, were current (past 30 days) cigarette smokers, or were high-intensity cigarette smokers. We fit multivariable logistic regression models among baseline non-cigarette smokers to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with subsequent cigarette smoking initiation and current cigarette smoking, accounting for established sociodemographic and behavioral risk factors. We fit similarly specified multivariable ordinal logistic regression models to assess whether baseline water pipe tobacco smoking and baseline snus use were associated with high-intensity cigarette smoking at follow-up.Water pipe tobacco smoking and the use of snus at baseline.Among baseline non-cigarette smokers, cigarette smoking initiation, current (past 30 days) cigarette smoking at follow-up, and the intensity of cigarette smoking at follow-up.Among 1596 respondents, 1048 had never smoked cigarettes at baseline, of whom 71 had smoked water pipe tobacco and 20 had used snus at baseline. At follow-up, accounting for behavioral and sociodemographic risk factors, baseline water pipe tobacco smoking and snus use were independently associated with cigarette smoking initiation (adjusted odds ratios: 2.56; 95% CI, 1.46-4.47 and 3.73; 95% CI, 1.43-9.76, respectively), current cigarette smoking (adjusted odds ratios: 2.48; 95% CI, 1.01-6.06 and 6.19; 95% CI, 1.86-20.56, respectively), and higher intensity of cigarette smoking (adjusted proportional odds ratios: 2.55; 95% CI, 1.48-4.38 and 4.45; 95% CI, 1.75-11.27, respectively).Water pipe tobacco smoking and the use of snus independently predicted the onset of cigarette smoking and current cigarette smoking at follow-up. Comprehensive Food and Drug Administration regulation of these tobacco products may limit their appeal to youth and curb the onset of cigarette smoking.
Project description:PURPOSE:The molecular epidemiology of most EGFR and KRAS mutations in lung cancer remains unclear. EXPERIMENTAL DESIGN:We genotyped 3,026 lung adenocarcinomas for the major EGFR (exon 19 deletions and L858R) and KRAS (G12, G13) mutations and examined correlations with demographic, clinical, and smoking history data. RESULTS:EGFR mutations were found in 43% of never smokers and in 11% of smokers. KRAS mutations occurred in 34% of smokers and in 6% of never smokers. In patients with smoking histories up to 10 pack-years, EGFR predominated over KRAS. Among former smokers with lung cancer, multivariate analysis showed that, independent of pack-years, increasing smoking-free years raise the likelihood of EGFR mutation. Never smokers were more likely than smokers to have KRAS G > A transition mutation (mostly G12D; 58% vs. 20%, P = 0.0001). KRAS G12C, the most common G > T transversion mutation in smokers, was more frequent in women (P = 0.007) and these women were younger than men with the same mutation (median 65 vs. 69, P = 0.0008) and had smoked less. CONCLUSIONS:The distinct types of KRAS mutations in smokers versus never smokers suggest that most KRAS-mutant lung cancers in never smokers are not due to second-hand smoke exposure. The higher frequency of KRAS G12C in women, their younger age, and lesser smoking history together support a heightened susceptibility to tobacco carcinogens.
Project description:Importance:An increasing proportion of US smokers smoke at low intensity and not every day. Some nondaily smokers have always had this pattern, whereas others previously smoked daily. The effect of reducing the level of smoking from daily to nondaily smoking and the dose response at low smoking levels are poorly understood. Objective:To evaluate risk of all-cause and cause-specific mortality among nondaily and daily cigarette smokers, by cigarettes per month, years after reducing from daily to nondaily smoking, and years since quitting. Design, Setting, and Participants:A prospective cohort study using harmonized data from multiple cycles of the Tobacco Use Supplements to the Current Population Survey (TUS-CPS), linked to the National Death Index, were analyzed during the period from 2018 to 2020. Adults completed the 1992-1993, 1995-1996, 1998-1999, 2000, 2001-2002, 2003, 2006-2007, or 2010-2011 TUS-CPS. Cigarette smokers were classified as daily or nondaily users; current nondaily smokers were further categorized by whether they previously smoked every day. Main Outcomes and Measures:Hazard ratios (HRs) and 95% CIs for risks of mortality vs never smoking. Age was the underlying time metric, adjusted for sex, race/ethnicity, education, survey year, and household income. Results:Among 505?500 participants (aged 18-103 years), approximately 47?000 deaths occurred. The median number of cigarettes smoked per month was 600 (interquartile range, 300-600) (20 cigarettes per day [interquartile range, 10-20 cigarettes per day]) for daily cigarette smokers and 40 (interquartile range, 15-90) for lifelong nondaily smokers. Nevertheless, both current daily (HR, 2.32; 95% CI, 2.25-2.38) and lifelong nondaily (HR, 1.82; 95% CI, 1.65-2.01) smokers had higher all-cause mortality risks than never smokers. Associations were observed for 6 to 10 cigarettes per month and increased with greater-intensity use. Nondaily smokers who previously smoked every day had lower mortality risks than daily smokers, with similar HRs after 10 or more years of nondaily smoking as lifelong nondaily smokers (HR vs never smokers, 1.73; 95% CI, 1.56-1.92). Yet, their risks were higher than former smokers who quit 10 or more years before (HR vs never smokers, 1.18; 95% CI, 1.15-1.22). Conclusions and Relevance:Although reducing smoking from daily to nondaily was associated with decreased mortality risk, cessation was associated with far greater benefit. Lifelong nondaily smokers have higher mortality risks than never smokers, even among those smoking 6 to 10 cigarettes per month. Thus, all smokers should quit, regardless of how infrequently they smoke.
Project description:Cigar and pipe smoking are considered risk factors for head and neck cancers, but the magnitude of effect estimates for these products has been imprecisely estimated. By using pooled data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium (comprising 13,935 cases and 18,691 controls in 19 studies from 1981 to 2007), we applied hierarchical logistic regression to more precisely estimate odds ratios and 95% confidence intervals for cigarette, cigar, and pipe smoking separately, compared with reference groups of those who had never smoked each single product. Odds ratios for cigar and pipe smoking were stratified by ever cigarette smoking. We also considered effect estimates of smoking a single product exclusively versus never having smoked any product (reference group). Among never cigarette smokers, the odds ratio for ever cigar smoking was 2.54 (95% confidence interval (CI): 1.93, 3.34), and the odds ratio for ever pipe smoking was 2.08 (95% CI: 1.55, 2.81). These odds ratios increased with increasing frequency and duration of smoking (Ptrend ? 0.0001). Odds ratios for cigar and pipe smoking were not elevated among ever cigarette smokers. Head and neck cancer risk was elevated for those who reported exclusive cigar smoking (odds ratio = 3.49, 95% CI: 2.58, 4.73) or exclusive pipe smoking (odds ratio = 3.71, 95% CI: 2.59, 5.33). These results suggest that cigar and pipe smoking are independently associated with increased risk of head and neck cancers.
Project description:Tobacco smoking causes DNA damages in epithelial cells and immune dysfunction in the lung, which collectively contribute to lung carcinogenesis and progression. However, potential mechanisms by which tumor-infiltrating immune cells contribute to lung cancer survival and their differential contributions in ever-smokers and never-smokers are not well studied. Here, we performed integrative analysis of 11 lung cancer gene-expression datasets, including 1,111 lung adenocarcinomas and 200 adjacent normal lung samples. Distinct pathways were altered in lung carcinogenesis in ever-smokers and never-smokers. Never-smoker patients had a better outcome than ever-smoker patients. We characterized compositional patterns of 21 types of immune cells in lung adenocarcinomas and revealed the complex association between immune cell composition and clinical outcomes. Interestingly, we found two subsets of immune cells, mast cells and CD4+ memory T cells, which had completely opposite associations with outcomes in resting and activated status. We further discovered that several chemokines and their associated receptors (e.g., CXCL11-CX3CR1 axis) were selectively altered in lung tumors in response to cigarette smoking and their abundances showed stronger correlation with fractions of these immune subsets in ever-smokers than never-smokers. The status switched from the resting to activated forms in mast cells and CD4+ memory T cells might manifest some important processes induced by cigarette smoking during tumor development and progression. Our findings suggested that aberrant activation of mast cells and CD4+ memory T cells plays crucial roles in cigarette smoking-induced immune dysfunction in the lung, which contributes to tumor development and progression.
Project description:OBJECTIVE:To prospectively examine vaping as a predictor of future cigarette smoking among youth with and without previous cigarette smoking experience. A secondary aim is to investigate whether vaping may desensitise youth to the dangers of smoking. METHODS:Analysis of prospective longitudinal panel data from the nationally representative Monitoring the Future study. The analysis is based on 347 12th grade students who were part of a randomly selected subsample that completed in-school surveys in 2014 and were resurveyed 1-year later. RESULTS:Among youth who had never smoked a cigarette by 12th grade, baseline, recent vapers were more than 4 times (relative risk (RR)=4.78) more likely to report past-year cigarette smoking at follow-up, even among youth who reported the highest possible level of perceived risk for cigarette smoking at baseline. Among 12th grade students who had smoked in the past but had not recently smoked at baseline, recent vapers were twice (RR=2.15) as likely to report smoking in the past 12?months at the follow-up. Vaping did not predict cessation of smoking among recent smokers at baseline. Among never-smokers at baseline, recent vapers were more than 4 times (RR=4.73) more likely to move away from the perception of cigarettes as posing a 'great risk' of harm, a finding consistent with a desensitisation process. CONCLUSIONS:These results contribute to the growing body of evidence supporting vaping as a one-way bridge to cigarette smoking among youth. Vaping as a risk factor for future smoking is a strong, scientifically-based rationale for restricting youth access to e-cigarettes.
Project description:OBJECTIVES:Although the smoking prevalence continues to decline in New Zealand (NZ) overall, little is known about smoking in university students. A 2013 survey of students aged 17-25 years found that 14% were current smokers, and 3% daily smokers. However, the sample did not include students from all NZ universities. This study examines the prevalence and patterns of cigarette smoking among students aged 18-24 years. SETTING:University students across NZ. METHODS:Data came from a March to May 2018 survey of students from all NZ universities, and were weighted to account for undersampling and oversampling, based on gender and university size. ?2 tests were used to compare smoking by age, gender and ethnicity. PARTICIPANTS:1476 participants were included: 919 (62.3%) aged 18-20 years and 557 (37.7%) aged 21-24 years; 569 (38.6%) male and 907 (61.4%) female; and 117 (7.9%) M?ori and 1359 (92.1%) non-M?ori. RESULTS:49.8% (95% CI 47.2 to 52.4) of respondents reported ever smoking, 11.1% (95% CI 9.5 to 12.9) currently smoked (smoked at least once a month) and 5.9% (95% CI 4.8 to 7.3) smoked at least daily (daily smokers). Of current smokers, 63.6% smoked 1-5 cigarettes/day, 45.8% smoked daily, 73.4% smoked first cigarette >60?min after waking, 86.0% never/almost never smoked in indoor and 64.6% in outdoor smokefree spaces, 69.9% planned to quit and 32.4% had tried to quit. Ever, current and daily smoking were significantly higher in 21-24 compared with 18-20?years olds, and in males compared with females. Older participants were more likely to report smoking more cigarettes/day. M?ori were more likely to report ever smoking than non-M?ori. CONCLUSIONS:Current smoking among NZ university students aged 18-24 years appears to be declining but daily smoking could be increasing. However, many students appeared less addicted to nicotine, and willing to quit. We recommend increasing the availability of smokefree services for students who wish to quit.
Project description:To examine how the relative size of six groups of male ever snus users (current and former users of snus who were current, former or never cigarette smokers) varied over time in Norway, and how these groups differ with regard to important measures of tobacco behaviour.Repeated cross-sectional nationally representative surveys of tobacco use. The association between survey year and the six categories of ever snus use was examined using cross-tabulation and multinomial logistic regression. Differences in tobacco behaviour across snus use categories were examined using logistic and ordinary least squares (OLS) regression.Norway, 2003-15.A total of 2067 males aged 15-79 years.The categories of ever snus use represented all six combinations of cigarette smoking (current, former or never) among current and former users of snus. The variables measuring tobacco behaviour were: order of product uptake (snus or cigarettes first), mean cigarette consumption, reduction from daily to occasional smoking, intention to quit cigarettes, future smoking identity and use of snus in latest quit attempt.During the period 2003-15, the relative share of current snus users who had never smoked, and current snus users who were former smokers, increased. The share of dual users, and smokers who were former snus users, decreased. Among men who reported life-time experience with both products, a large majority had initiated their tobacco use with cigarettes. The average number of cigarettes smoked weekly was lower among dual users compared with current smokers who were former snus users or had never used snus.During the period 2003-15 in Norway, which has a mature snus market, even though smoking has declined and the relative size of the category of never-smokers among male users of snus has increased, the majority of snus users are still former or current smokers.
Project description:OBJECTIVE:Use of electronic cigarettes (e-cigarettes) is prevalent among adolescents, but there is little knowledge about the consequences of their use. We examined, longitudinally, how e-cigarette use among adolescents is related to subsequent smoking behaviour. METHODS:Longitudinal school-based survey with a baseline sample of 2338 students (9th and 10th graders, mean age 14.7?years) in Hawaii surveyed in 2013 (time 1, T1) and followed up 1?year later (time 2, T2). We assessed e-cigarette use, tobacco cigarette use, and psychosocial covariates (demographics, parental support and monitoring, and sensation seeking and rebelliousness). Regression analyses including the covariates tested whether e-cigarette use was related to the onset of smoking among youth who had never smoked cigarettes, and to change in smoking frequency among youth who had previously smoked cigarettes. RESULTS:Among T1 never-smokers, those who had used e-cigarettes at T1 were more likely to have smoked cigarettes at T2; for a complete-case analysis, adjusted OR=2.87, 95% CI 2.03 to 4.05, p<0.0001. Among ever-smokers at T1, using e-cigarettes was not related to significant change in their frequency of smoking at T2. Uptake of e-cigarette use among T1 never-users of either product was predicted by age, Caucasian or Native Hawaiian (vs Asian-American) ethnicity, lower parental education and parental support, higher rebelliousness, and perception of e-cigarettes as healthier. CONCLUSIONS:Adolescents who use e-cigarettes are more likely to start smoking cigarettes. This result together with other findings suggests that policies restricting adolescents' access to e-cigarettes may have a rationale from a public health standpoint.