Association Of Lung Cancer Risk Research Articles

Association of Lung Cancer Risk With the Presence of Both Lung Nodules and Emphysema in a Lung Cancer Screening Trial.

The coexistence of emphysema and lung nodules could interact with each other and then lead to potential higher lung cancer risk. The study aimed to explore the association between emphysema combined with lung nodules and lung cancer risk. A total of 21,949 participants from the National Lung Screening Trial (NLST) who underwent low-dose computed tomography (LDCT) examination were included. Participants were categorized into four groups (NENN group (non-emphysema and non-nodules), E group (emphysema without nodules), N group (nodules without emphysema), and E + N group (nodules with emphysema)) according to whether there were lung nodules and emphysema. Multivariable Cox regression and stratified analyses were performed to estimate the association between the four groups and lung cancer risk. Among the 21,949 participants, there were 9,040 (41.2%), 5,819 (26.5%), 4,737 (21.6%), and 2,353 (10.7%) participants in the NENN group, E group, N group, and E + N group. The risk of lung cancer incidence increased in turn in NENN group, E group, N group and E + N group. Compared with NENN group, the age-adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of lung cancer incidence were 2.07 (1.69 - 2.54) for E group, 4.13 (3.47 - 5.05) for N group, and 6.26 (5.14 - 7.62) for E + N group. The association was robust to adjustment for potential confounders (1.83 (1.47 - 2.27) for E group, 3.97 (3.24 - 4.86) for N group, and 5.23 (4.28 - 6.48) for E + N group). Comparable results as the lung cancer incidence were observed for lung cancer mortality, whether in age-adjusted model (E group: 1.85 (1.39 - 2.46), N group: 2.49 (1.89 - 3.29), E + N group: 4.27 (3.21 - 5.68)) or fully adjusted model (E group: 1.56 (1.15 - 2.11), N group: 2.43 (1.81 - 3.26), E + N group: 3.39 (2.50 - 4.61)). However, the trend of all-cause mortality risk among the four groups was somewhat different from that of lung cancer risk, whether in age-adjusted model (1.37 (1.21 - 1.54) for E group, 1.06 (0.92 - 1.21) for N group, and 1.75 (1.51 - 2.02) for E + N group) or fully adjusted model (1.26 (1.10 - 1.44) for E group, 1.09 (0.94 - 1.27) for N group, and 1.52 (1.30 - 1.79) for E + N group). Based on a large-scale lung cancer screening trial in the United States, this study demonstrated that either emphysema or lung nodules can increase lung cancer risk, and lung nodules combined with emphysema can further increase the lung cancer risk and all-cause mortality. The significance of these findings for lung cancer screening should be evaluated.

Dairy product consumption and lung cancer risk: A prospective analysis

Current evidence on prospective associations between dairy product, dairy fat and lactose intakes and lung cancer risk is limited and inconsistent. We conducted a prospective analysis of associations of lung cancer risk with dairy product intakes in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort. Pre-diagnostic dairy product intake was assessed through a validated Diet History Questionnaire. All incident lung cancer cases were pathologically verified. Multivariable Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) for associations of lung cancer risk with intakes of total, full-fat, low-fat dairy, fermented or non-fermented dairy products; milk fat content preference; and intakes of total and saturated fats and lactose from dairy products. Among 101,709 adults (mean age of 65.5 years), a total of 1583 lung cancer cases were identified during 1,167,239 person-years of follow up. Mean total dairy product intake was 156g/1000 kilocalories (kcal), including 20g/1000kcal from fermented dairy products. Total dairy intake was not associated with lung cancer risk (HR [95% CI]=1.03 [0.89-1.18]) comparing the highest quartile with the lowest. Fermented dairy intake was inversely associated with lung cancer risk (0.85 [0.72-0.99]). In contrast, there were no statistically significant associations with low-fat, full-fat or non-fermented dairy product intakes. The preference of whole milk when consuming milk as beverage was associated with a higher risk of lung cancer than the preference of <0.5% fat milk (1.24 [1.03-1.49]). Total fat, saturated fat and lactose intakes from dairy products each were not associated with lung cancer risk. Our results suggest an inverse association of lung cancer risk with fermented dairy intake and a positive association with the whole milk preference in a US population. Future studies exploring underlying molecular mechanisms are warranted.

Calcium Intake and Lung Cancer Risk: A Pooled Analysis of 12 Prospective Cohort Studies

BackgroundPrevious studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to the differences in intake amounts and contributing sources of calcium and smoking prevalence. ObjectivesWe investigated the associations of lung cancer risk with intake of calcium from foods and/or supplements and major calcium-rich foods in 12 studies. MethodsData from 12 prospective cohort studies conducted in the United States, Europe, and Asia were pooled and harmonized. We applied the DRI to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intake. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall HR (95% CI). ResultsAmong 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 y. Overall, the dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98–1.18) for higher (>1.5 RDA) and 1.01 (0.95–1.07) for lower intake (<0.5 RDA) comparing with recommended intake (EAR to RDA). Milk and soy food intake were positively or inversely associated with lung cancer risk [HR (95% CI) = 1.07 (1.02–1.12) and 0.92 (0.84–1.00)], respectively. The positive association with milk intake was significant only in European and North American studies (P-interaction for region = 0.04). No significant association was observed for calcium supplements. ConclusionsIn this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

Associations of Dietary Intakes of Carotenoids and Vitamin A with Lung Cancer Risk in a Low-Income Population in the Southeastern United States.

Simple SummaryLung cancer is the second most common cancer and the leading cause of cancer death in the U.S. It is critical to identify the risk factors for lung cancer. However, previous results on the associations of dietary carotenoids and vitamin A intakes with lung cancer risk were inconclusive, and the study populations were mainly European descendants and Asians. This study aimed to prospectively investigate the associations among low-income African Americans and European Americans using resources from the Southern Community Cohort Study. Our findings suggested positive associations between dietary vitamin A intake and lung cancer risk among current smokers and racial-specific associations between dietary vitamin A intake and adenocarcinoma risk. Our study may contribute to understanding the role of nutrient intakes and lung cancer associations among the underrepresented study populations and improving the risk assessment of lung cancer risk.Observational studies found inverse associations of dietary carotenoids and vitamin A intakes with lung cancer risk. However, interventional trials among high-risk individuals showed that β-carotene supplements increased lung cancer risk. Most of the previous studies were conducted among European descendants or Asians. We prospectively examined the associations of lung cancer risk with dietary intakes of carotenoids and vitamin A in the Southern Community Cohort Study, including 65,550 participants with 1204 incident lung cancer cases. Multivariate Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Lung cancer cases had lower energy-adjusted dietary intakes of all carotenoids and vitamin A than non-cases. However, dietary intakes of carotenoids and vitamin A were not associated with overall lung cancer risk. A significant positive association of dietary vitamin A intake with lung cancer risk was observed among current smokers (HRQ4 vs. Q1 = 1.23; 95% CI: 1.02–1.49; Ptrend = 0.01). In addition, vitamin A intake was associated with an increased risk of adenocarcinoma among African Americans (HRQ4 vs. Q1 = 1.55; 95%CI: 1.08–2.21; Ptrend = 0.03). Dietary lycopene intake was associated with an increased risk of lung cancer among former smokers (HRQ4 vs. Q1 = 1.50; 95% CI: 1.04–2.17; Ptrend = 0.03). There are positive associations of dietary β-cryptoxanthin intake with squamous carcinoma risk (HRQ4 vs. Q1 = 1.49; 95% CI: 1.03–2.15; Ptrend = 0.03). Further studies are warranted to confirm our findings.

Associations of lung cancer risk with biomarkers of Helicobacter pylori infection.

Helicobacter pylori infection has been suggested to be associated with lung cancer risk. However, information is lacking on whether the association differs by H. pylori antigen. We conducted a nested case-control study within the Southern Community Cohort Study, including 295 incident lung cancer cases and 295 controls. Helicobacter pylori multiplex serology assay was performed to detect antibodies to 15 H. pylori proteins. Conditional logistic regression was used to estimate odds ratios (ORs) and confidence intervals (95% CIs) after adjustment for covariates. Overall H. pylori+ was associated with a non-statistically significant increased risk of lung cancer (OR: 1.29; 95% CI: 0.85-1.95). Significant associations, however, were observed for H. pylori+ VacA+ (OR: 1.64; 95% CI: 1.02-2.62) and H. pylori+ Catalase+ (OR: 1.75; 95% CI: 1.11-2.77). The positive association of H. pylori+ Catalase+ with lung cancer risk was predominantly seen among African Americans (OR: 2.09; 95% CI: 1.11-3.95) but not European Americans (OR: 1.20; 95% CI: 0.56-2.54). Among participants who smoked ≥ 30 pack-years, overall H. pylori+ (OR: 1.85; 95% CI: 1.02-3.35), H. pylori+ CagA+ (OR: 2.77; 95% CI: 1.35-5.70), H. pylori+ VacA+ (OR: 2.53; 95% CI: 1.25-5.13) and H. pylori+ HP1564+ (OR: 2.01; 95% CI: 1.07-3.77) were associated with increased risk of lung cancer. Our study provides novel evidence that associations of H. pylori infection with lung cancer risk differ by H. pylori biomarker, may be more evident among African Americans and may be modified by smoking habits. Furthermore, studies are warranted to confirm our findings.

Lung cancer risk following previous abnormal chest radiographs: A 27-year follow-up study of a Chinese lung screening cohort.

Background Chest radiograph (CXR) is still one of the most commonly used diagnostic tools for chest diseases. In this cohort study, we attempted to investigate the magnitude and temporal pattern of lung cancer risk following abnormal CXR findings.MethodsWe conducted an extended follow‐up of an occupational screening cohort in Yunnan, China. The associations between abnormal CXR results from baseline screening, the first four consecutive rounds of CXR screening, all previous rounds of screening and lung cancer risk were analyzed using time‐varying coefficient Cox regression model. The associations of lung cancer risk and previous CXR‐screening results according to histology were also considered. Sensitivity analyses were conducted to assess the robustness of the previous abnormal CXR findings on subsequent lung cancer risk.ResultsAbnormal CXR findings were associated with a significantly increased lung cancer risk. This relative hazard significantly decreased over time. Compared to negative screening results, the adjusted hazard ratios (HR) of baseline abnormal CXR results, and at least one abnormal result in the first four consecutive screening rounds during the first 5 years of follow‐up were 17.06 (95% CI: 11.74–24.79) and 13.77 (95%: 9.58–17.79), respectively. This significantly increased lung cancer risk continued over the next 5 years. These associations were stronger for persistent abnormal findings, and abnormal findings identified in recent screening rounds.ConclusionsThe increased risk was significant for both squamous cell carcinoma and adenocarcinoma. Although decreased over time, an increased lung cancer risk relative to abnormal CXR findings can continue for 10 years.

Variation in oral microbiome is associated with future risk of lung cancer among never-smokers

ObjectiveTo prospectively investigate whether diversity in oral microbiota is associated with risk of lung cancer among never-smokers.Design and settingA nested case–control study within two prospective cohort studies, the Shanghai Women’s...

Abstract 4609: TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk

Abstract Background: Lung cancer is the leading cause of cancer-related death in men and women, and cigarette smoking is the most significant preventable risk factor. Early detection through annual low dose CT screening reduces mortality but has low positive predictive value and specificity, in part due to low lung cancer incidence (&amp;lt;10%) among those who currently meet screening criteria. Thus, there is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effectivescreening. The purpose of this study was to test the hypothesis that high risk for lung cancer is characterized by high prevalence of low variant allele frequency (VAF) somatic mutations among known lung cancer driver genes in normal airway epithelial cells (AEC). Methods: Synthetic DNA internal standards (IS) were prepared for each of 11 lung cancer driver genes and mixed with each AEC genomic (g)DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach enabled reliable detection of mutations with VAF as low as 5 x 10-4 (0.05%). This method was then applied in a retrospective case-control study. Specifically, AEC specimens were collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested. Results: TP53 mutations with 0.05-1.0% VAF were more prevalent (p&amp;lt;0.005) and significantly more enriched for tobacco smoke and age-associated mutation signatures in AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls. Conclusions: Measurement of very low frequency mutations in the 0.05-1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes. Citation Format: Daniel J. Craig, Thomas Morrison, Sadik Khuder, Erin L. Crawford, Leihong Wu, Joshua Xu, Thomas M. Blomquist, James C. Willey. TP53, PIK3CA, and BRAF somatic mutations in airway epithelial field of injury associated with lung cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4609.

Abstract 1052: Associations of Helicobacter pylori biomarkers with lung cancer risk among low-income and African American populations: Results from the Southern Community Cohort Study

Abstract Lung cancer is the leading cause of cancer death in the United States and many other countries. Helicobacter pylori (H. pylori), a Group 1 carcinogen classified by IARC, is a common bacteria infecting humans. Emerging evidence supports a possible etiological role of H. pylori infection in lung cancer. H. pylori has evolved over time to become highly genetically diverse, with substantial variations in the presence or levels of virulence factors. To evaluate the associations of lung cancer risk with H. pylori seropositivity, overall and by antigen-specific biomarkers, we conducted a nested case-control study using resources from the Southern Community Cohort Study (SCCS) including ~86,000 participants, two-thirds of whom are African American. A total of 295 incident lung cancer cases and 295 matched controls were included in this study. Controls were matched to cases on age, sex, race, recruitment site and date of blood draw. H. pylori multiplex serology assay was performed to detect levels of IgA, IgM and IgG antibodies to 15 H. pylori proteins. Overall H. pylori seropositivity (H. pylori+) was defined as being positive to any 4 or more H. pylori antigens. Individual H. pylori antigens were considered as seropositive only when the sample was simultaneously considered overall H. pylori+, which ensured that antigen-specific seropositivity was not based on cross-reactive antibody responses from infection with other pathogens expressing homologous proteins. Multivariable logistic regression models were used to estimate odds ratios (ORs) and corresponding confidence intervals (95% CIs) for lung cancer risk associated with seropositivity of H. pylori after adjusting for age, smoking status, pack-years, alcohol consumption, education, household income, BMI and history of COPD. Overall H. pylori+ was associated with a non-statistically significant increased lung cancer risk (OR, 1.29; 95% CI, 0.85-1.95). Associations were stronger for H. pylori+ VacA+ (OR, 1.64; 95% CI, 1.02-2.62) and H. pylori+ Catalase+ (OR, 1.75; 95% CI, 1.11-2.77), the latter more so among African Americans (OR, 2.09; 95% CI, 1.11-3.95) than European Americans (OR, 1.20; 95% CI, 0.56-2.54). Among people who smoked ≥ 30 pack-years, overall H. pylori+ (OR, 1.85; 95% CI, 1.02-3.35), H. pylori+ CagA+ (OR, 2.77; 95% CI, 1.35-5.70), H. pylori+ VacA+ (OR, 2.53; 95% CI, 1.25-5.13) and H. pylori+ Omp+ (OR, 2.01; 95% CI, 1.07-3.77) were associated with increased lung cancer risk. Among current and former smokers, significant interactions were observed for H. pylori+ CagA+ (p for interaction = 0.01) and H. pylori+ VacA+ (p for interaction = 0.03) between those who smoked ≥ 30 pack-years and those who smoked &amp;lt; 30 pack-years. In summary, our results indicate that H. pylori infection may be associated with an elevated risk of lung cancer, and the associated risk might differ by antigen-specific H. pylori biomarkers and smoking amount. Further studies are warranted to confirm our findings. Citation Format: Hyung-Suk Yoon, Wei Zheng, Hui Cai, Jie Wu, Wanqing Wen, Regina Courtney, Angelika Michel, Michael Pawlita, Tim Waterboer, Qiuyin Cai. Associations of Helicobacter pylori biomarkers with lung cancer risk among low-income and African American populations: Results from the Southern Community Cohort Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1052.

Technical advance in targeted NGS analysis enables identification of lung cancer risk-associated low frequency TP53, PIK3CA, and BRAF mutations in airway epithelial cells

BackgroundStandardized Nucleic Acid Quantification for SEQuencing (SNAQ-SEQ) is a novel method that utilizes synthetic DNA internal standards spiked into each sample prior to next generation sequencing (NGS) library preparation. This method was applied to analysis of normal appearing airway epithelial cells (AEC) obtained by bronchoscopy in an effort to define a somatic mutation field effect associated with lung cancer risk. There is a need for biomarkers that reliably detect those at highest lung cancer risk, thereby enabling more effective screening by annual low dose CT. The purpose of this study was to test the hypothesis that lung cancer risk is characterized by increased prevalence of low variant allele frequency (VAF) somatic mutations in lung cancer driver genes in AEC.MethodsSynthetic DNA internal standards (IS) were prepared for 11 lung cancer driver genes and mixed with each AEC genomic (g) DNA specimen prior to competitive multiplex PCR amplicon NGS library preparation. A custom Perl script was developed to separate IS reads and respective specimen gDNA reads from each target into separate files for parallel variant frequency analysis. This approach identified nucleotide-specific sequencing error and enabled reliable detection of specimen mutations with VAF as low as 5 × 10− 4 (0.05%). This method was applied in a retrospective case-control study of AEC specimens collected by bronchoscopic brush biopsy from the normal airways of 19 subjects, including eleven lung cancer cases and eight non-cancer controls, and the association of lung cancer risk with AEC driver gene mutations was tested.ResultsTP53 mutations with 0.05–1.0% VAF were more prevalent (p < 0.05) and also enriched for tobacco smoke and age-associated mutation signatures in normal AEC from lung cancer cases compared to non-cancer controls matched for smoking and age. Further, PIK3CA and BRAF mutations in this VAF range were identified in AEC from cases but not controls.ConclusionsApplication of SNAQ-SEQ to measure mutations in the 0.05–1.0% VAF range enabled identification of an AEC somatic mutation field of injury associated with lung cancer risk. A biomarker comprising TP53, PIK3CA, and BRAF somatic mutations may better stratify individuals for optimal lung cancer screening and prevention outcomes.

Food intake of folate, folic acid and other B vitamins with lung cancer risk in a low-income population in the Southeastern United States.

We prospectively examined associations of lung cancer risk with food intake of B vitamins involved in one-carbon metabolism and the use of folic acid-containing supplements among a low-income population of black and white adults in the Southeastern US. Within the Southern Community Cohort Study, we included 1064 incident lung cancer cases among 68,236 participants aged 40-79years at study enrollment. Food intake and the use of folic acid-containing supplements were assessed using a validated food frequency questionnaire at study enrollment. Multivariate Cox regression was used to estimate hazards ratios (HRs) and the 95% confidence intervals (CIs). Folate and/or folic acid intake from food were not associated with lung cancer risk; HRs (95% CI) for highest compared with lowest quartile were 1.08 (0.91-1.29) for total dietary folate, 1.00 (0.84-1.19) for food folate, and 1.09 (0.91-1.30) for food folic acid, respectively. Similarly, no associations were observed after stratifying by sex, race and smoking status, except for a positive association with total dietary folate intake among black women (HR 1.46, 95% CI 1.04-2.05 for the highest quartile compared with the lowest quartile, P trend = 0.02). Neither the use of folic acid-containing supplements nor food intake of vitamin B6, vitamin B12 and riboflavin were associated with lung cancer risk. Our findings do not support a protective effect of folate or folic acid for lung cancer prevention in a low-income population of black and white adults in the Southeastern US. Our finding of a positive association with total dietary folate intake among black women needs to be interpreted with caution and replicated in other studies.

The Association of Vitamin D Receptor Gene Polymorphism with Lung Cancer Risk: An Update Meta-analysis.

The association between vitamin D receptor (VDR) genetic polymorphism and lung cancer risk has been evaluated by the previous meta-analyses. Due to the emergence of novel studies and inappropriate inclusion of overlapping populations, an updated meta-analysis on recent evidences is necessarily needed. We comprehensively searched databases of PubMed, Web of Science and Chinese National Knowledge Infrastructure and finally obtained 7 eligible studies according to the inclusion criteria. Four positions on VDR gene, namely ApaI (rs7975232), BsmI (rs1544410), FokI (rs10735810) and TaqI (rs731236), were considered in this investigation. Data pooling found no significant association of lung cancer risk with ApaI or FokI. In contrast, it was indicated that the BsmI A allele was negatively related to the lung cancer risk, compared with the G allele (OR = 0.51, 95% CI = 0.33-0.79). Individuals with BsmI AA (OR = 0.53, 95% CI = 0.26-1.11) and AG genotypes (OR = 0.46, 95% CI = 0.30-0.71) showed decreased risk of lung cancer, compared with those of GG genotype. Regarding the TaqI polymorphism, the T allele carriers were at increased risk of lung cancer (OR = 1.25, 95% CI = 1.04-1.50). Compared with the TaqI TC+CC genotype, the TT genotype was positively associated with lung cancer risk (OR = 1.42, 95% CI = 1.11-1.82). No publication bias was identified in any of the analysis. In conclusion, VDR genetic polymorphism may be correlated to lung cancer risk. Given limited number of the included studies, more observations are warranted to draw a safer conclusion.

Helicobacter pylori and Systemic Disease.

Helicobacter pylori and Systemic Disease.

XRCC1 gene polymorphisms and lung cancer susceptibility: a meta-analysis of 44 case–control studies

X-ray repair cross-complementing group 1 gene (XRCC1) has been implicated in risk for lung cancer. However, the results from different studies remain controversial. In this meta-analysis, we have assessed 44 published case-control studies regarding associations of lung cancer risk with three common polymorphisms, codon 194, codon 280 and codon 399, and -77 T > C in the promoter region of XRCC1. The results in total population showed that the risk for lung cancer was increased among the variant homozygote Trp/Trp of codon 194 polymorphism, compared with the wild type Arg/Arg (OR: 1.19; 95 % CI 1.01-1.39), and the variant genotype CC of -77 T > C polymorphism showed a significantly increased risk of developing lung cancer, compared to wild-type genotype TT (OR: 1.91; 95 % CI 1.24-2.94). However, no associations were found between lung cancer risk and codon 280, codon 399. In the subgroup analyses by ethnicity, the OR for the variant homozygote Trp/Trp of codon 194 was 1.21(95 % CI 1.02-1.43) for Asian. When stratified by source of control, we found a protective effect of codon 194 Arg/Trp genotype (OR: 0.87; 95 % CI 0.77-0.98) and risk effect of codon 399 combined Arg/Gln + Gln/Gln variant genotype (OR: 1.09; 95 % CI 1.01-1.18) for lung cancer on the basis of hospital control. Subgroup analyses by histological types of lung cancer indicated that the heterozygote Arg/Trp in codon 194 could decrease and the combined variant genotype Arg/Gln + Gln/Gln in codon 399 could increase the risk of non-small cell lung cancer (OR: 0.69; 95 % CI 0.57-0.85 and OR: 1.14; 95 % CI 1.04-1.24). In conclusion, this meta-analysis has demonstrated that codon 194, codon 399 and -77 T > C polymorphisms of XRCC1 gene might have contributed to individual susceptibility to lung cancer. To further evaluate effect of XRCC1 polymorphisms, gene-gene interaction and gene-environment interaction on lung cancer risk, a single large sample size study with thousands of subjects is required to get conclusive results.

New associations of the genetic polymorphisms in nicotinic receptor genes with the risk of lung cancer

AimsPrevious studies revealed association of lung cancer risk with single nucleotide polymorphisms (SNPs) in chromosome 15q25 region containing CHRNA5–CHRNA3–CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster. The genetic variations in other lung nAChRs remained unknown. In this study, we perform case-control analysis of CHRNA9 and CHRNA3 genes using 340 non-small cell lung cancer cases and 435 controls. Main methodsAll exons, 3′UTR, intron 1 and parts of other introns surrounding exons 2–5 of CHRNA9 gene as well as exons 2, 3 of CHRNA3 gene and parts of surrounding intronic regions were sequenced. The study was controlled for gender, age and ethnicity related differences. Each SNP in analyzed groups was assessed by allele frequency, genotype distribution and haplotype analysis. Key findingsThe case-control analysis revealed that an increased risk is associated with two SNPs in CHRNA9, rs56159866 and rs6819385, and one in CHRNA3, rs8040868. The risk was reduced for three SNPs in CHRNA9, rs55998310, rs56291234, and newly discovered rs182073550, and also in carriers of the haplotype NP_060051.2 containing ancestral N442 variant of α9. SignificanceThe nonsynonymous substitutions can produce receptors exhibiting unique ligand-binding and downstream signaling characteristics, synonymous as well all intronic SNPs may affect protein production at the transcriptional and/or translational levels, or just manifest association with cancer by genetic linkage to other alleles. Elucidation of the mechanisms by which individual genetic variations in α9 affect predisposition to lung cancer may lead to development of personalized approaches to cancer prevention and treatment as well as protection against tobacco consumption.

Dietary Patterns Affect Lung Cancer Risk in Never Smokers

A number of studies suggest a role of dietary factors as risk predictors of lung cancer in never smokers. However, it is difficult to interpret the observed associations of lung cancer risk with any particular dietary item due to high correlation among different dietary items. In this study, we derived uncorrelated patterns of dietary items in the never smokers and evaluated the association of these patterns with lung cancer risk, using food frequency data from 299 never-smoker lung cancer patients and 317 controls enrolled in an ongoing case–control lung cancer study. We identified 2 major dietary patterns in never smokers: a “healthy eating” pattern including vegetables, fruits, and low-fat food items, and a “mixed dishes” pattern including most foods with positive loadings. Using multivariable regression analysis, we show that the healthy eating pattern is associated with a significant reduction of lung cancer risk among never smokers. The effect of the healthy eating pattern remained significant after adjustment for age, gender, education, caloric intake, secondhand smoke exposure, and family history of cancer. This finding, if confirmed in a prospective study, has a clear preventive significance, by promoting interventions encouraging healthier diets.

Abstract 1911: Dietary intake of riboflavin and risk of lung cancer among non-smokers: A prospective cohort study among Chinese women

Abstract Lung cancer is the leading cause of cancer death in the United States and many other countries. A significant subset of lung cancers is not associated with smoking, and risk factors for these cancers remain unclear. Riboflavin (vitamin B2), a water-soluble vitamin, is involved in vital metabolic processes and is necessary for normal cell function, growth, and energy production. Riboflavin is the central component of the flavin mononucleotide (FMN) and flavin dinucleotide (FAD), coenzymes for a wide variety of oxidative enzymes. We prospectively examined the association of dietary intake of riboflavin with lung cancer risk in the Shanghai Women's Health Study cohort. A total of 73,237 women aged 40-70 years and free of cancer at enrollment were included in this analysis. Usual dietary intake was assessed at baseline (1997-2000) through in-person interviews by using a validated food-frequency questionnaire. We used Cox proportional hazards regression to estimate the relative risks (RR) and 95% confidence intervals (CI) for the association of lung cancer risk with dietary riboflavin consumption. In 665,554 person-years of follow-up, we identified 328 lung cancer cases, of which 303 were non-smokers. Dietary intake of riboflavin was inversely associated with lung cancer risk. The RRs (95% CI) of developing lung cancer among non-smokers decreased with increasing quintiles of riboflavin intake (P for trend = 0.007) from 1.0 to 1.01 (0.73-1.42), 0.77 (0.53-1.13), 0.81 (0.55-1.20), and 0.51 (0.31-0.83) for the lowest to highest quintiles. Exclusion of 51 cases diagnosed within two years of follow-up did not change the HR estimations appreciably. Further, adjusting for dietary intakes of other B vitamins (B1, B6, B12, niacin, and folate) and methionine did not meaningfully affect the HR estimates. No statistically significant associations were found for other B vitamins. In summary, our findings among non-smoking Chinese women suggest that dietary intake of riboflavin may reduce the risk of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1911. doi:10.1158/1538-7445.AM2011-1911

P.6.c.003 Association of the CHRNA5-A3-B4 gene cluster with heaviness of smoking

Previous studies revealed association of lung cancer risk with single nucleotide polymorphisms (SNPs) in chromosome 15q25 region containing CHRNA5–CHRNA3–CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster. The genetic variations in other lung nAChRs remained unknown. In this study, we perform case-control analysis of CHRNA9 and CHRNA3 genes using 340 non-small cell lung cancer cases and 435 controls.All exons, 3′UTR, intron 1 and parts of other introns surrounding exons 2–5 of CHRNA9 gene as well as exons 2, 3 of CHRNA3 gene and parts of surrounding intronic regions were sequenced. The study was controlled for gender, age and ethnicity related differences. Each SNP in analyzed groups was assessed by allele frequency, genotype distribution and haplotype analysis.The case-control analysis revealed that an increased risk is associated with two SNPs in CHRNA9, rs56159866 and rs6819385, and one in CHRNA3, rs8040868. The risk was reduced for three SNPs in CHRNA9, rs55998310, rs56291234, and newly discovered rs182073550, and also in carriers of the haplotype NP_060051.2 containing ancestral N442 variant of α9.The nonsynonymous substitutions can produce receptors exhibiting unique ligand-binding and downstream signaling characteristics, synonymous as well all intronic SNPs may affect protein production at the transcriptional and/or translational levels, or just manifest association with cancer by genetic linkage to other alleles. Elucidation of the mechanisms by which individual genetic variations in α9 affect predisposition to lung cancer may lead to development of personalized approaches to cancer prevention and treatment as well as protection against tobacco consumption.

Family History of Cancer and Risk of Lung Cancer among Nonsmoking Chinese Women

The relationship between family cancer history in first-degree relatives and risk of lung cancer was evaluated among a population-based cohort of 71,392 female nonsmokers in Shanghai, China. A total of 179 newly diagnosed lung cancer patients were identified during 441,410 person-years of follow-up. Lung cancer risk was not elevated among those with a family history of lung cancer. However, risk of lung cancer was increased among subjects who had two or more first-degree relatives with any type of cancers {rate ratio [RR], 1.95 [95% confidence intervals (95% CI), 1.08-3.54] for two relatives with any cancers and RR, 3.17 [95% CI, 1.00-10.03] for three or more relatives with any cancer}. Having a family history of colorectal cancer (RR, 2.38; 95% CI, 1.21-4.70) and having siblings with stomach cancer (RR, 2.16; 95% CI, 1.01-4.65) and pancreatic cancer (RR, 4.19; 95% CI, 1.04-16.95) were also found to be associated with lung cancer risk. This cohort study indicated a moderate association of lung cancer risk with a family cancer history in general, but not with a family history of lung cancer specifically. The associations were stronger when a sibling, rather than a parent, was affected. The apparent link between lung cancer risk and a family history of colorectal, stomach, and pancreas cancers may be worth further investigation.

DNA Repair and Cell Cycle Control Genes and the Risk of Young-Onset Lung Cancer

Exposure to tobacco smoke and to mutagenic xenobiotics can cause various types of DNA damage in lung cells, which, if not corrected by DNA repair systems, may lead to deregulation of the cell cycle and, ultimately, to cancer. Genetic variation could thus be an important factor in determining susceptibility to tobacco-induced lung cancer with genetic susceptibility playing a larger role in young-onset cases compared with that in the general population. We have therefore studied 102 single-nucleotide polymorphisms (SNP) in 34 key DNA repair and cell cycle control genes in 299 lung cancer cases diagnosed before the age of 50 years and 317 controls from six countries of Central and Eastern Europe. We have found no association of lung cancer risk with polymorphisms in genes related to cell cycle control, single-strand/double-strand break repair, or base excision repair. Significant associations (P < 0.05) were found with polymorphisms in genes involved in DNA damage sensing (ATM) and, interestingly, in four genes encoding proteins involved in mismatch repair (LIG1, LIG3, MLH1, and MSH6). The strongest associations were observed with heterozygote carriers of LIG1 -7C>T [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.13-2.64] and homozygote carriers of LIG3 rs1052536 (OR, 2.05; 95% CI, 1.25-3.38). Consideration of the relatively large number of markers assessed diminishes the significance of these findings; thus, these SNPs should be considered promising candidates for further investigation in other independent populations.