Genetic polymorphism of the human cytochrome CYP2A13 in a French population: implication in lung cancer susceptibility

The human cytochrome CYP2A13, which is mainly expressed in the respiratory tract, has been shown to be highly efficient in vitro in the metabolism of tobacco-smoke carcinogens and procarcinogens such as 4-methylnitroso-1-(3-pyridyl)-1-butanone (NNK). In order to investigate the extent of CYP2A13 genetic polymorphism in a French Caucasian population of 102 individuals, a screening for sequence variations in the 5'-untranslated and protein encoding regions of its gene was performed using a polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) strategy. Six polymorphisms in the coding region were identified, including two rare missense mutations (C474G or Asp158Glu, G967T or Val323Leu) and one nonsense mutation (Arg101Stop). This deleterious mutation, the most frequent (5%) in our population, presumably encodes a severely truncated protein. The influence of the nonsense mutation in lung cancer susceptibility was examined by PCR-SSCP using peripheral blood DNA from 204 cases of lung cancer and 201 controls. The CYP2A13*7 allele, which harbours the C301T mutation, was present in 2.0% of controls and 3.4% of cases. However, multivariate analysis showed an elevated risk for small cell lung cancer in subjects heterozygous for the null allele (odds ratio OR=9.9; 95% confidence interval CI=1.9-52.2). This increased risk was not linked to other histological types of lung cancer.     

CYP1A1 genetic polymorphisms, tobacco smoking and lung cancer risk in a French Caucasian population

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Microsomal epoxide hydrolase polymorphisms and lung cancer risk: a quantitative review

To investigate the role of microsomal epoxide hydrolase (mEH) polymorphisms in the aetiology of lung cancer and to assess the interaction between mEH polymorphisms and smoking, we performed a meta-analysis of seven published studies, which included 2078 cases and 3081 controls, and a pooled analysis of eight studies (four published and four unpublished at that time) with a total of 986 cases and 1633 controls. The combined metaanalysis odds ratios (ORs) were 0.98 (95% confidence interval [CI] = 0.72-1.35) for polymorphism at amino acid 113 in exon 3 (His/His versus Tyr/Tyr genotype) and 1.00 (95% CI= 0.71-1.41) for polymorphism at amino acid 139 in exon 4 (Arg/Arg versus His/ His genotype). In the pooled analysis, we observed a significant decrease in lung cancer risk (OR = 0.70, 95% CI = 0.51-0.96) for exon 3 His/His genotype after adjustment for age, sex, smoking and centre. The protective effect of exon 3 polymorphism seems stronger for adenocarcinoma of the lung than for other histological types. The OR for high predicted mEH activity, compared with low activity, was 1.54 (95% CI = 0.77-3.07) in the meta analysis and 1.18 (95% CI = 0.92-1.52) in the pooled analysis. We did not find a consistent modification of the carcinogenic effect of smoking according to mEH polymorphism, although the risk of lung cancer decreased among never smokers with high mEH activity and among heavy smokers with the exon 3 His/His genotype. In conclusion, this study suggests a possible effect of mEH polymorphisms at exon 3 in modulating lung cancer. If present, this effect may vary among different populations, possibly because of interaction with genetic or environmental factors.     

Microsomal epoxide hydrolase polymorphisms and lung cancer risk: a quantitative review

To investigate the role of microsomal epoxide hydrolase (mEH) polymorphisms in the aetiology of lung cancer and to assess the interaction between mEH polymorphisms and smoking, we performed a meta-analysis of seven published studies, which included 2078 cases and 3081 controls, and a pooled analysis of eight studies (four published and four unpublished at that time) with a total of 986 cases and 1633 controls. The combined metaanalysis odds ratios (ORs) were 0.98 (95% confidence interval [CI] = 0.72-1.35) for polymorphism at amino acid 113 in exon 3 (His/His versus Tyr/Tyr genotype) and 1.00 (95% CI= 0.71-1.41) for polymorphism at amino acid 139 in exon 4 (Arg/Arg versus His/ His genotype). In the pooled analysis, we observed a significant decrease in lung cancer risk (OR = 0.70, 95% CI = 0.51-0.96) for exon 3 His/His genotype after adjustment for age, sex, smoking and centre. The protective effect of exon 3 polymorphism seems stronger for adenocarcinoma of the lung than for other histological types. The OR for high predicted mEH activity, compared with low activity, was 1.54 (95% CI = 0.77-3.07) in the meta analysis and 1.18 (95% CI = 0.92-1.52) in the pooled analysis. We did not find a consistent modification of the carcinogenic effect of smoking according to mEH polymorphism, although the risk of lung cancer decreased among never smokers with high mEH activity and among heavy smokers with the exon 3 His/His genotype. In conclusion, this study suggests a possible effect of mEH polymorphisms at exon 3 in modulating lung cancer. If present, this effect may vary among different populations, possibly because of interaction with genetic or environmental factors.     

Genetic variation in ESR2 and estrogen receptor-beta expression in lung tumors

Objective: To investigate the association between inherited variation in the estrogen receptor beta (ERβ) gene (ESR2) and ERβ lung tumor expression, a phenotype that possibly affects survival differently in men and women. Methods: We genotyped 135 lung cancer patients for 22 ESR2 single nucleotide polymorphisms (SNPs) and measured nuclear and cytoplasmic ERβ expression by immunohistochemistry (IHC) in their primary lung tumor. Distributing Allred ERβ IHC scores according to ESR2 genotype classified under a dominant genetic model, we used rank sum tests to identify ESR2 SNPs significantly associated (p < 0.05) with ERβ expression. Results: 35%, 35%, and 29% of lung tumors showed no/low (Allred < 6), intermediate (Allred 6–7), and maximal (Allred 8) cytoplasmic ERβ expression, whereas 13%, 27%, and 60% showed no/low, intermediate, and maximal nuclear ERβ expression. For SNPs rs8021944, rs1256061 and rs10146204, ERβ expression was higher according to the rank sum test in lung tumors from patients with at least one minor allele. For each of these three SNPs, the odds of maximal (Allred 8) relative to no/low (Allred < 6) ERβ expression was 3-fold higher in tumors from patients with at least one minor allele than in tumors from patients homozygous for the common allele. Conclusion: Inherited variability in ESR2 may determine ERβ lung tumor expression.     

CYP1A1 genetic polymorphisms,tobacco smoking and lung cancer risk in a French Caucasian population

The CYP1A1 gene encoding for an enzyme involved in the metabolic activation of important tobacco carcinogens could be implicated in smoking-induced lung cancer. Given the strong association between tobacco smoking and lung cancer, the effect of tobacco smoke exposure has to be taken into account when studying the potential association between lung cancer and CYP1A1 genotypes. The effect of two CYP1A1 genetic polymorphisms (Mspl and IIe-Val) on lung cancer risk were evaluated using peripheral blood DNA from 150 lung cancer patients and 171 controls. The Mspl sitepresent allele was found among 19.3% of both cases and controls and the variant allele Val among 6.7% of cases and 8.8% of controls. Lung cancer risks associated with the Mspl site-present allele (OR= 0.9; 95%Cl: 0.5-1.8) or with the Val allele (OR= 0.8; 95%Cl: 0.3-1.9) were not increased after adjustment for tobacco and asbestos exposures. These results persisted when analyses were stratified on smoking status, daily consumption of tobacco or duration of smoking. Similar findings were obtained when squamous cell or small cell carcinomas were studied separately. This study thus suggests a minor role for the known CYP1A1 gene polymorphisms in predisposition to lung cancer among Caucasian populations.     

Methyl-CpG binding domain 1 gene polymorphisms and lung cancer risk in a Chinese population

Polymorphisms of the methyl-CpG binding domain 1 (MBD1) gene may influence MBD1 activity on gene expression profiles, thereby modulating individual susceptibility to lung cancer. To test this hypothesis, we investigated the associations of four MBD1 polymorphisms and lung cancer risk in a Chinese population. Single locus analysis revealed significant associations between two polymorphisms (rs125555 and rs140689) and lung cancer risk (p=0.011 and p=0.005, respectively). Since the two polymorphisms were in linkage disequilibrium, further haplotype analyses were performed and revealed a significant association with lung cancer (global test p-value=0.0041). Our results suggested that MBD1 polymorphisms might be involved in the development of lung cancer. Validation of these findings in larger studies of other populations is needed.     

Association between CASP3 polymorphisms and overall cancer risk: A meta-analysis of case-control studies

Several studies inspected the relationship between caspase-3 (CASP3) polymorphisms and the risk of several human cancers, but the findings remain controversial. We conducted a meta-analysis aiming to inspect the association between CASP3 rs1049216 T>C, rs12108497 C>T, rs4647603 G>A, rs4647602 C>A, rs6948 T>G, rs2705897 A>C, and rs113420705 G>A polymorphisms and cancer risk. Eligible studies were recognized by searching the Web of Science, PubMed, Scopus, and Google Scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to quantitatively evaluate the association between each polymorphism of CASP3 and cancer risk. The rs4647603 variant significantly increased the risk of cancer in an overdominant (OR, 1.44; 95% CI, 1.03-2.01; P = 0.03; AG vs AA+GG) inheritance model. Regarding the rs4647602 variant, the findings revealed that this variant was associated with protection against cancer in homozygous codominant (OR, 0.67; 95% CI, 0.56-0.80; P < 0.00001; AA vs CC), dominant (OR, 0.84; 95% CI, 0.73-0.96; P = 0.009; AC+AA vs CC), recessive (OR, 0.70; 95% CI, 0.61-0.79; P < 0.00001; AA vs AC+CC), and allele (OR, 0.81; 95% CI, 0.75-0.88; P = 0.00001; A vs C) models. The findings suggested that the rs2705897 variant significantly decreased the risk of cancer in heterozygous codominant (OR, 0.80; 95% CI, 0.67-0.94; P = 0.009; AC vs AA), dominant (OR, 0.81; 95% CI, 0.69-0.95; P = 0.009; AC+CC vs AA), overdominant (OR, 0.80; 95% CI, 0.68-0.95; P = 0.01; AC vs CC+AA), and allele (OR, 0.85; 95% CI, 0.74-0.97; P = 0.02; C vs A) models. The results did not support an association between CASP3 rs1049216 and rs6948 polymorphisms and cancer risk. In summary, the findings of this meta-analysis support an association between CASP3 polymorphisms and cancer risk. Larger and well-designed studies are desired to evaluate these associations in detail.     

Genetic polymorphisms of cytokine genes and risk for trichloroethylene-induced severe generalized dermatitis: A case-control study

Trichloroethylene (TCE)-induced severe generalized dermatitis (SGD) is considered to be a contact allergic disease and is dependent on a cell-mediated immune response. Little is known about its pathogenesis. Several lines of evidence suggest that tumour necrosis factor (TNF) and interleukin 4 (IL-4) are involved in the immunological and inflammatory reactions. To investigate the relation between polymorphisms of TNF and the IL-4 gene and the risk of TCE-induced SGD, a case-control study was conducted consisting of 111 patients diagnosed with SGD and 152 TCE-exposed workers without SGD. Polymerase chain reaction-restriction fragment length polymorphism was used to detect the polymorphisms of TNF-α (G-238A, G-308A), TNF-β (intron 1) and IL-4 (C-590T). Logistic regression was applied to calculate the odds ratios (OR) and 95% confidence intervals. The results reveal that the frequency of TNF α-308 wild allele in cases was significantly higher than that in control subjects (p=0.049). Individuals with a heterozygous genotype of TNF α-308 were associated with the decreased risk of TCE-induced SGD relative to the homozygous genotype (OR=0.398, 95% CI=0.164–0.967). No significant differences in the allele and genotype frequencies could be demonstrated at any other polymorphic loci among both groups. The finding of a possible contribution of a TNF-α genetic polymorphism is a primary result because the pathogenesis of TCE-induced SGD is complex and likely to involve the interaction of a number of genes. A further study should be conducted to illustrate the influence of a link between certain relevant alleles in the assessment of genetic susceptibility.     

Active cigarette smoking and the risk of breast cancer: a cohort study

BackgroundTobacco use has been implicated in the etiology of a large number of cancers, and there exists substantial biological plausibility that it could also be involved in breast carcinogenesis. Despite this, epidemiological evidence to date is inconsistent. The aim of this study was to investigate the role of active smoking and the risk of incident, invasive breast cancer using a prospective cohort of women from the Canadian Study of Diet, Lifestyle and Health.MethodsUsing a case-cohort design, an age-stratified subcohort of 3314 women was created from 39,532 female participants who returned completed self-administered lifestyle and dietary questionnaires at baseline. A total of 1096 breast cancer cases were identified in the entire cohort (including 141 cases from the subcohort) by linkage to the Canadian Cancer Registry. Cox regression models were used to estimate hazard ratios for the association between the different smoking exposures and the risk of breast cancer, using a modification for the case-cohort design.ResultsAfter carefully considering early-life exposures and potential confounders, we found no association between any smoking exposure and risk of breast cancer in this study (Hazard ratio = 1.00, 95% confidence interval = 0.87–1.17 for ever vs never smokers).ConclusionsAlthough these results cannot rule out an association between smoking and breast cancer, they do agree with the current literature suggesting that, if an association does exist, it is relatively weak.     

Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men

PurposeTranslesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.MethodsWe evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case–control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.ResultsCarriers of the G allele of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR) = 0.62, 95% confidence interval (CI): 0.44–0.89), comparing with those carrying the C allele, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR = 0.47, 95% CI: 0.25–0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533–rs5744724) haplotype had decreased risk of lung cancer (OR = 0.69, 95% CI: 0.49–0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygote of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard radio (HR) 1.54 (95% CI: 1.12–2.12) and 1.44 (95% CI: 1.06–1.97) respectively.ConclusionsOur findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.     

Association between paraoxonase-1 gene Q192R and L55M polymorphisms and risk of gastric cancer: A case-control study from Iran

The aim of the present study was to examine the relation between two paraoxonase1 (PON1) polymorphisms, Q192R and L55M and susceptibility to gastric cancer in an Iranian population. In this case-control study the PON1 polymorphisms were assessed in 90 gastric cancer patients and 90 healthy controls by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method. Regarding PON1 Q192R polymorphism, a significant increase in the R allele in the patient group compared with the controls (p value?=?0.0006) While the Q allele was more frequent in the control group. No significant difference was found in the genotype or allele frequency of the L55M polymorphism between healthy individuals and patients with gastric cancer. Our results demonstrated the protective effect of Q allele against gastric cancer.     

Occupation and risk of prostate cancer in Canadian men: A case-control study across eight Canadian provinces

BackgroundThe etiology of prostate cancer continues to be poorly understood, including the role of occupation. Past Canadian studies have not been able to thoroughly examine prostate cancer by occupation with detailed information on individual level factors.MethodsOccupation, industry and prostate cancer were examined using data from the National Enhanced Cancer Surveillance System, a large population-based case-control study conducted across eight Canadian provinces from 1994 to 1997. This analysis included 1737 incident cases and 1803 controls aged 50 to 79 years. Lifetime occupational histories were used to group individuals by occupation and industry employment. Odds ratios and 95% confidence intervals were calculated and adjustments were made for known and possible risk factors.ResultsBy occupation, elevated risks were observed in farming and farm management (OR = 1.37, 95% CI 1.02–1.84), armed forces (OR = 1.33, 95% CI 1.06-1.65) and legal work (OR = 2.58, 95% CI 1.05–6.35). Elevated risks were also observed in office work (OR = 1.20, 95% CI 1.00–1.43) and plumbing (OR = 1.77, 95% CI 1.07–2.93) and with ≥10 years duration of employment. Decreased risks were observed in senior management (OR = 0.65, 95% CI 0.46–0.91), construction management (OR = 0.69, 95% CI 0.50–0.94) and travel work (OR = 0.37, 95% CI 0.16–0.88). Industry results were similar to occupation results, except for an elevated risk in forestry/logging (OR = 1.54, 95% CI 1.06–2.25) and a decreased risk in primary metal products (OR = 0.70, 95% CI 0.51–0.96).ConclusionThis study presents associations between occupation, industry and prostate cancer, while accounting for individual level factors. Further research is needed on potential job-specific exposures and screening behaviours.     

Antiestrogen use in breast cancer patients reduces the risk of subsequent lung cancer: A population-based study

BackgroundThere is accumulating epidemiological and preclinical evidence that estrogen might be a driver of lung cancer. Breast cancer survivors can offer a unique patient cohort to examine the effect of antiestrogen therapy on lung cancer carcinogenesis because many of these women would have received long-term selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) as adjuvant treatment. Our hypothesis is that estrogens play a role in lung cancer development, and that antiestrogen therapy would affect the incidence of subsequent lung cancer among breast cancer survivors.MethodsUsing the Taiwan National Health Insurance (NHI) database, the study included 40,900 survivors of non-metastatic breast cancer after primary surgery, and most antiestrogen users complied well with the medication regimen. We evaluate the effect of antiestrogen therapy on the incidence of subsequent lung cancers.ResultsThis population-based study revealed that antiestrogen use in breast cancer patients was associated with a reduced risk of subsequent lung cancer in older patients (≥50 years) (HR 0.73, 95%CI 0.54–0.99) when compared with breast cancer survivors who did not use antiestrogens.ConclusionThe study supports the hypothesis that antiestrogen therapy modifies lung cancer carcinogenesis in older women. Further well-designed clinical trials to explore the potential of antiestrogens in lung cancer prevention and treatment would be worthwhile.     

Combined effect of GSTM1, GSTT1 and GSTP1 polymorphisms on histological subtypes of lung cancer

Genetic polymorphisms are natural genetic variations in the gene sequence that occur at a frequency of >1% in the population. This genetic variability (polymorphisms) can be a factor in cancer risk. The functional polymorphisms in GST genes play an important role in susceptibility to lung cancer. In our previous study, we reported that the combination of certain genotypes of GSTM1, GSTT1 and CYP1A1 is associated with lung cancer. The study has been extended to investigate the potential role of polymorphism in GSTP1 alone or in combination with the status of GSTM1 and GSTT1 genes in the likelihood of development of lung cancer. A total of 302 subjects (151 cases and 151 controls) were evaluated. Using a case–control design, individuals were genotyped for GSTs using multiplex polymerase chain reaction and restriction fragment length polymorphism techniques. The data obtained were analyzed using multiple logistic regression. The combined ‘at risk’ genotypes of GSTM1 null and GSTT1 null in comparison with ‘wild-type’ genotypes seems to be associated with a greater risk of lung cancer, but the results are not significant (odds ratio (OR) 2.0, 95% confidence interval (CI) 0.68–5.96) and for squamous cell carcinoma (SqCC) it was 1.6-fold (OR 1.6, 95% CI 0.49–5.68). In summary, our case–control study of lung cancer revealed that the effect of these polymorphisms is not very marked for different genotypic combinations of GSTP1, GSTM1 and GSTT1 in the context of developing lung cancer in a north Indian population. However, the increased risk was limited to SqCC, and was not found for other histological subtypes. Further analyses on this topic are needed.     

Association between lung cancer screening and smoking cessation

IntroductionAdults with high-risk smoking histories benefit from annual lung cancer screening. It is unclear if there is an association between lung cancer screening and smoking cessation among U.S. adults who receive screening.MethodsWe performed this population-based cross-sectional study using data from the Behavioral Risk Factor Surveillance System (2017–2020). We defined individuals eligible for lung cancer screening as adults 55–80 years old with ≥ 30 pack-year smoking history who were currently smoking or quit within the last 15 years. We assessed the association between lung cancer screening and current smoking status.ResultsBetween 2017 and 2020, 12,382 participants met screening criteria. Current smoking was reported by 5685 (45.9 %) participants, of whom 40.4 % (2298) reported a cessation attempt in the prior year. Lung cancer screening was reported by only 2022 (16.3 %) eligible participants. Lung cancer screening was associated with lower likelihood of currently smoking (odds ratio [OR] 0.705, 95 % CI 0.626–0.793) compared to individuals who did not receive screening. Screening was also associated with higher likelihood of reporting a cessation attempt in the prior year (OR 1.562, 95 % CI 1.345–1.815) compared to individuals who did not receive screening.ConclusionsReceipt of lung cancer screening was associated with lower smoking rates and more frequent cessation attempts among U.S. adults. Better implementation of lung cancer screening programs is critical and may profoundly increase smoking cessation in this population at risk of developing lung cancer.     

Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study

BackgroundThere is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders.MethodsTwenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type.ResultsWe observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10–19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12–15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for ≥20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90).ConclusionsWhether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms.     

The value of blood-based measures of liver function and urate in lung cancer risk prediction: A cohort study and health economic analysis

BackgroundSeveral studies have reported associations between low-cost blood-based measurements and lung cancer but their role in risk prediction is unclear. We examined the value of expanding lung cancer risk models for targeting low-dose computed tomography (LDCT), including blood measurements of liver function and urate.MethodsWe analysed a cohort of 388,199 UK Biobank participants with 1873 events and calculated the c-index and fraction of new information (FNI) for models expanded to include combinations of blood measurements, lung function (forced expiratory volume in 1 s - FEV₁), alcohol status and waist circumference. We calculated the hypothetical cost per lung cancer case detected by LDCT for different scenarios using a threshold of ≥ 1.51 % risk at 6 years.ResultsThe c-index was 0.805 (95 %CI:0.794–0.816) for the model containing conventional predictors. Expanding to include blood measurements increased the c-index to 0.815 (95 %CI: 0.804–0.826;p < 0.0001;FNI:0.06). Expanding to include FEV₁, alcohol status, and waist circumference increased the c-index to 0.811 (95 %CI: 0.800–0.822;p < 0.0001;FNI: 0.04). The c-index for the fully expanded model containing all variables was 0.819 (95 %CI:0.808–0.830;p < 0.0001;FNI:0.09). Model expansion had a greater impact on the c-index and FNI for people with a history of smoking cigarettes relative to the full cohort. Compared with the conventional risk model, the expanded models reduced the number of participants meeting the criteria for LDCT screening by 15–21 %, and lung cancer cases detected by 7–8 %. The additional cost per lung cancer case detected relative to the conventional model was £ 1018 for adding blood tests and £ 9775 for the fully expanded model.ConclusionBlood measurements of liver function and urate made a modest improvement to lung cancer risk prediction compared with a model containing conventional risk factors. There was no evidence that model expansion would improve the cost per lung cancer case detected in UK healthcare settings.