Although lung cancer is the leading cause of cancer death in women, few studies have investigated the hormonal influence on survival after a lung cancer diagnosis and results have been inconsistent. We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non–small-cell lung cancer (NSCLC).
Population-based lung cancer cases diagnosed between November 1, 2001 and October 31, 2005 were identified through the Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry. Interview and follow-up data were collected for 485 women. Cox proportional hazard regression models were used to determine hazard ratios (HRs) for death after an NSCLC diagnosis associated with reproductive and hormonal variables.
Use of hormone therapy (HT) was associated with improved survival (HR, 0.69; 95% confidence interval, 0.54–0.89), adjusting for stage, surgery, radiation, education level, pack-years of smoking, age at diagnosis, race, and a multiplicative interaction between stage and radiation. No other reproductive or hormonal factor was associated with survival after an NSCLC diagnosis. Increased duration of HT use before the lung cancer diagnosis (132 months or longer) was associated with improved survival (HR, 0.54; 95% confidence interval, 0.37–0.78), and this finding remained significant in women taking either estrogen alone or progesterone plus estrogen, never smokers, and smokers.
These findings suggest that HT use, in particular use of estrogen plus progesterone, and long-term HT use are associated with improved survival of NSCLC.
Non-small-cell lung cancer; Hormone use; Survival
With increasing numbers of communities harmed by exposures to toxic substances, greater understanding of the psychosocial consequences of these technological disasters is needed. One community living the consequences of a slow-motion technological disaster is Libby, Montana, where, for nearly 70 years, amphibole asbestos-contaminated vermiculite was mined and processed. Former mine employees and Libby area residents continue to cope with the health consequences of occupational and environmental asbestos exposure and with the psychosocial challenges accompanying chronic and often fatal asbestos-related diseases (ARD). Nine focus groups were conducted with Libby area residents. Transcripts were analyzed to explore patterns of family communication about ARD. The following five patterns emerged: Open/Supportive, Silent/Supportive, Open/Conflictual, Silent/Conflictual, and Silent/Denial. Open/Supportive communication included encouragement to be screened for ARD, information about ARD and related disaster topics, and emotional support for people with ARD. In contrast, communication patterns characterized by silence or conflict have the potential to hinder health-promoting communication and increase psychological distress.
environmental hazard; technological disaster; family; communication; asbestos
Three genome-wide association studies identified a region on chromosome 15q25.1 associated with lung cancer and measures of nicotine addiction. This region includes nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5. These studies were conducted in European or European American populations and do not provide risk estimates for African Americans. The goal of this study was to determine whether recently identified genetic variation in 3 SNPs (rs1051730, rs931794, rs8034191) on chromosome 15q25.1 contributes to risk of lung cancer in African Americans.
Data were derived from three case-control studies. Participants included 1058 population-based non-small cell lung cancer cases selected from the Detroit area SEER registry and 1314 controls matched within study by age, race, and sex. Thirty-nine percent of participants were African American.
Risk associated with rs1051730 (odds ratio 1.59; 95% confidence interval 1.16–2.19) and rs931794 (odds ratio 1.39; 95% confidence interval 1.09–1.78) increased in ever smoking African Americans adjusting for cigarettes smoked per day. Among white cases, the number of cigarettes smoked varied by genotype at all three SNPs, and when smoking quantity was included in the models, risk was not significantly associated with any of the three SNPs.
These findings suggest that SNPs in the CHRNA3 and CHRNA5 region contribute to lung cancer risk, and while variant alleles are less frequent in African Americans, risk in this group may be greater than in whites and less likely to reflect an indirect effect on lung cancer risk through nicotine dependence.
Non-small cell lung cancer; Smoking; SNPs
Chronic obstructive pulmonary disease (COPD) and lung cancer represent two diseases that share a strong risk factor in smoking, and COPD increases risk of lung cancer even after adjusting for the effects of smoking. These diseases not only occur jointly within an individual but also there is evidence of shared occurrence within families. Understanding the genetic contributions to these diseases, both individually and jointly, is needed to identify the highest risk group for screening and targeted prevention, as well as aiding in the development of targeted treatments. The chromosomal regions that have been identified as being associated either jointly or independently with lung cancer, COPD, nicotine addiction, and lung function are presented. Studies jointly measuring genetic variation in lung cancer and COPD have been limited by the lack of detailed COPD diagnosis and severity data in lung cancer populations, the lack of lung cancer–specific phenotypes (histology and tumor markers) in COPD populations, and the lack of inclusion of minorities. African Americans, who smoke fewer cigarettes per day and have different linkage disequilibrium and disease patterns than whites, and Asians, also with different patterns of exposure to lung carcinogens and linkage patterns, will provide invaluable information to better understand shared and independent genetic contributions to lung cancer and COPD to more fully define the highest risk group of individuals who will most benefit from screening and to develop molecular signatures to aid in targeted treatment and prevention efforts.
lung cancer; COPD; smoking; genetics
Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population.
The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained.
Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women.
AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women.
Epidemiology; Ovarian cancer; African American; Case–control study
Since January 2008, the National Institutes of Health (NIH) has required that all investigators who receive NIH support submit de-identified high-throughput genomic data to the database of Genotypes and Phenotypes (dbGaP). The purpose of this study was to explore the feasibility of re-consenting participants from three inactive studies, conducted from 2000 through 2009, to submit their data to dbGaP.
Participants were those enrolled in one of three prior population-based case-control studies of lung cancer who had given a DNA sample. Consent to release de-identified data to dbGaP took place via mailed forms and follow-up phone calls. Chi-squared tests were used to examine differences in re-contact and consent proportions between groups.
A total of 2,471 participants were initially eligible for re-contact. Six hundred and thirty-eight participants were found to be deceased (n = 627) or did not give permission to re-contact (n = 11). Of the 1,833 remaining participants, 42.3% provided written consent, 37.0% could not be located, 13.7% verbally agreed to have their data released but never returned written consent, 5.3% refused, and 1.6% were too ill at the time of contact. There were significant differences in ability to locate participants by age, race, gender, and case-control status; however, once located, there were no differences in re-consent rates.
This study demonstrates that while most previous study participants agreed to release data, a small proportion are opposed to submitting their data to dbGaP. In addition, it demonstrates the difficulty studies based on existing samples may have in locating inactive participants for re-consent.
Despite more aggressive screening across all demographics and gradual declines in mortality related to prostate cancer (PCa) in the United States, disparities among populations persist. A substantial proportion of African American men (AAM) have a higher overall incidence, earlier age of onset, increased proportion of clinically advanced disease, and increased bone metastases and mortality from PCa compared to European American men (EAM). Limited early evidence indicates that underlying causes for disparities may be observed in tumor-specific gene expression programs.
This study used microarray-based methods to measure expression levels for 517 genes that were previously associated with PCa in archived formalin-fixed paraffin embedded (FFPE) specimens; testing the hypothesis that gene expression features of functional consequence to cancer distinguish PCa from AAM and EAM. A t test was conducted comparing AAM to EAM expression levels for each probe on the array.
Analysis of 639 tumor samples (270 AAM, 369 EAM) showed that 95 genes were overexpressed specifically in PCa from AAM relative to EAM and 132 were overexpressed in PCa from EAM relative to AAM. Furthermore, systems-level analyses highlight the relevant signaling pathways and functions associated with the EAM- or AAM-specific overexpressed gene sets, for example, inflammation and lipid metabolism.
Results here bring further understanding to the potential for molecular differences for PCa in AAM versus EAM.
The results support the notion that therapeutic benefits will be realized when targeted treatments are designed to acknowledge and address a greater spectrum of PCa subtypes and molecular distinctions.
Germline apoptosis-related single nucleotide polymorphisms (SNPs) have been shown to
contribute to the risk of developing non-small cell lung cancer (NSCLC). However, very few studies
have looked specifically at apoptosis-related SNPs in a racially-stratified analysis of white and
We examined the risk of developing NSCLC associated with 98 germline SNPs in 32
apoptosis-related genes among women in a population-based case-control study from the Detroit
metropolitan area. We examined 453 cases of NSCLC and 478 control subjects. We used an unconditional
logistic regression with a dominant model, stratified by race, and adjusted for age, pack-years
smoked, ever/never smoking status, family history of lung cancer, history of COPD, BMI and
Our logistic regression identified 3 significant apoptosis-related SNPs in whites
(APAF-1, rs1007573; CD40 rs3765459, and CD40
rs1535045), and 7 significant SNPs (ATM, rs1801516; BAK1,
rs513349; TNF, rs1800629; TP63, rs6790167; TP63,
rs7613791, TP63, rs35592567 and TP63, rs3856775)
in African-Americans. In a downstream analysis, these SNPs were further prioritized utilizing the
False Positive Report Percentage (FPRP) methodology and backwards elimination. In whites,
APAF-1 (rs1007573), CD40 (rs3765459) and CD40
(rs1535045) were all found to be significant by FPRP. In African-Americans, TP63
SNPs rs6790167 and rs7613791 were found to have a significant FPRP. In parallel, a backward
elimination procedure was used on the 3 significant SNPs in whites and 7 significant SNPs in
African-Americans. This procedure identified APAF-1 rs1007573 (OR=1.86, 95% CI:
1.17-2.95) and CD40 rs1535045 (OR=0.58, 95% CI: 0.40-0.84) as significant
independent predictors of risk among whites, and ATM rs1801516 (OR=24.15, 95% CI:
3.50-166.55), TNF rs1800629 (OR= 0.42, 95% CI: 0.18-0.99) and TP63
rs6790167 (OR: 2.85, 95% CI: 1.33-6.09) as significant, independent predictors in
In whites, only SNPs APAF-1 rs1007573 and CD40
rs1535045 were significant by both FPRP and backwards elimination, while in African-Americans, only
TP63 rs6790167 was significant by both methodologies. Thus, we have identified
three promising variants associated with increased risk of NSCLC that warrant additional
investigation in future studies.
non-small cell lung cancer (NSCLC); single nucleotide polymorphisms; apoptosis; females; APAF-1; CD40; ATM; TNF; TP63
Black/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white lung cancer patients.
We therefore evaluated a panel of 1440 inflammatory gene variants in a two phase analysis (discovery and replication), added top GWAS lung cancer hits from Caucasian populations, and 28 SNPs from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases, 342 controls) was from the EXHALE study at Wayne State University.
In discovery, 154 inflammation SNPs were significant (P<0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, P=0.0013), and three GWAS hits, rs16969968 P=0.0014 and rs10519203 P=0.0003 in the 15q locus and rs2736100, the HTERT locus, P=0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46(1.14-1.87) in discovery, 1.37(1.05-1.77) in replication, and a combined OR of 1.40 (1.17-1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The AUC for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively.
As has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance.
Neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA5/CHRNA3/CHRNB4) have been reproducibly associated with nicotine dependence, smoking behaviors, and lung cancer risk. Of the few reports that have focused on early smoking behaviors, association results have been mixed. This meta-analysis examines early smoking phenotypes and SNPs in the gene cluster to determine: (1) whether the most robust association signal in this region (rs16969968) for other smoking behaviors is also associated with early behaviors, and/or (2) if additional statistically independent signals are important in early smoking. We focused on two phenotypes: age of tobacco initiation (AOI) and age of first regular tobacco use (AOS). This study included 56,034 subjects (41 groups) spanning nine countries and evaluated five SNPs including rs1948, rs16969968, rs578776, rs588765, and rs684513. Each dataset was analyzed using a centrally generated script. Meta-analyses were conducted from summary statistics. AOS yielded significant associations with SNPs rs578776 (beta = 0.02, P = 0.004), rs1948 (beta = 0.023, P = 0.018), and rs684513 (beta = 0.032, P = 0.017), indicating protective effects. There were no significant associations for the AOI phenotype. Importantly, rs16969968, the most replicated signal in this region for nicotine dependence, cigarettes per day, and cotinine levels, was not associated with AOI (P = 0.59) or AOS (P = 0.92). These results provide important insight into the complexity of smoking behavior phenotypes, and suggest that association signals in the CHRNA5/A3/B4 gene cluster affecting early smoking behaviors may be different from those affecting the mature nicotine dependence phenotype.
CHRNA5; CHRNA3; CHRNB4; meta-analysis; nicotine; smoke
Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31 and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans refined previous association signals by utilizing the reduced linkage disequilibrium observed in African-Americans.
1308 African-American cases and 1241 African-American controls from three centers were genotyped for 760 single nucleotide polymorphisms spanning three regions, and additional SNP imputation was performed. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.
The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution (rs16969968: OR = 1.57, 95% CI = 1.25–1.97, P = 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology-specific and included a missense variant in BAT2 associated with squamous-cell carcinoma (rs2736158: OR = 0.64, 95% CI = 0.48–0.85, P = 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR = 0.82, 95% CI = 0.73–0.93, P = 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR = 0.75, 95% CI = 0.65–0.86, P = 8.1 × 10−5).
Polymorphisms in 5p15.33, 6p22.1-p21.31 and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous-cell carcinoma.
Results implicate the BAT2, TERT and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.
Lung cancer; adenocarcinoma; squamous-cell carcinoma; fine-mapping; African-American; genetic association
Rational drug design based on molecular targets is starting to revolutionize cancer care. To maximize its potential for patients, a concomitant leveraging of molecular knowledge for selection of patients to future and current therapeutic options is paramount. The terms “individualized”, “personalized”, or “precision therapy” are currently used to describe these efforts. Here, we summarize current knowledge for selection of systemic targeted and cytotoxic therapy for patients with non-small-cell lung cancer. Based on this knowledge, we present a potential decision algorithm to best select patients for currently available therapies, which include the treatment options single-agent erlotinib or gefitinib, the ALK inhibitor crizotinib, double agent gemcitabine and platinum, double agent platinum and pemetrexed, and as a default option a taxane combined with a non-platinum drug, for instance a vinca alkaloid. The addition of bevacizumab to double-agent chemotherapy is also discussed. Currently available data on predictive biomarkers are largely based on subgroup or companion biomarker analyses of patient cohorts or clinical trials. Current and emerging markers must be incorporated prospectively into the design of clinical trials that test novel and established agents to better understand their clinical utility and to refine selection parameters and marker interactions. Future development will lead to increasing complexity in clinical decision making with substantial anticipated benefits to patients including increased therapeutic efficacy, reduced toxicity, and better quality of life.
Lung cancer; ERCC1; RRM1; TS; EGFR; EML4-ALK; Crizotinib; Bevacizumab
Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry, and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one novel locus at 5q33 (GALNT10, rs7708584, p=3.4×10−11) and another at 7p15 when combined with data from the Giant consortium (MIR148A/NFE2L3, rs10261878, p=1.2×10−10). We also found suggestive evidence of an association at a third locus at 6q16 in the African ancestry sample (KLHL32, rs974417, p=6.9×10−8). Thirty-two of the 36 previously established BMI variants displayed directionally consistent effect estimates in our GWAS (binomial p=9.7×10−7), of which five reached genome-wide significance. These findings provide strong support for shared BMI loci across populations as well as for the utility of studying ancestrally diverse populations.
Amplification of the fibroblast growth factor receptor 1 (FGFR1) gene has been described in tumors of non-small-cell lung cancer (NSCLC) patients. Prior reports showed conflicting rates of amplification frequency and clinical relevance.
Materials and Methods
We developed a reliable real-time quantitative PCR assay to assess the frequency of FGFR1 amplification and assessed the optimal cutoff level of amplification for clinical application.
In a training cohort of 203 NSCLCs, we established that a 3.5-fold amplification optimally divided patients into groups with different survival rates with a clear threshold level. Those with FGFR1 amplification levels above 3.5-fold had an inferior survival. These data were confirmed in a validation cohort of 142 NSCLC. After adjusting for age, sex, performance status, stage, and histology, patients with FGFR1 amplification levels above 3.5 fold had a hazard ratio of 2.91 (95% CI- 1.14, 7.41; pvalue-0.025) for death in the validation cohort. The rates of FGFR1 amplification using the cutoff level of 3.5 were 5.1% in squamous cell and 4.1% in adenocarcinomas. There was a non-significant trend towards higher amplifications rates in heavy smokers (> 15 pack-years of cigarette consumption) as compared to light smokers.
Our data suggest that a 3.5-fold amplification of FGFR1 is of clinical importance in NSCLC. Our cutpoint analysis showed a clear threshold effect for the impact of FGFR1 amplification on patients’ survival, which can be used as an initial guide for patient selection in trials assessing efficacy of novel FGFR inhibitors.
Adenocarcinoma of the pancreas is a significant cause of cancer mortality, and up to 10 % of cases appear to be familial. Heritable genomic copy number variants (CNVs) can modulate gene expression and predispose to disease. Here, we identify candidate predisposition genes for familial pancreatic cancer (FPC) by analyzing germline losses or gains present in one or more high-risk patients and absent in a large control group. A total of 120 FPC cases and 1,194 controls were genotyped on the Affymetrix 500K array, and 36 cases and 2,357 controls were genotyped on the Affymetrix 6.0 array. Detection of CNVs was performed by multiple computational algorithms and partially validated by quantitative PCR. We found no significant difference in the germline CNV profiles of cases and controls. A total of 93 non-redundant FPC-specific CNVs (53 losses and 40 gains) were identified in 50 cases, each CNV present in a single individual. FPC-specific CNVs overlapped the coding region of 88 RefSeq genes. Several of these genes have been reported to be differentially expressed and/or affected by copy number alterations in pancreatic adenocarcinoma. Further investigation in high-risk subjects may elucidate the role of one or more of these genes in genetic predisposition to pancreatic cancer.
To clarify the role of previous lung diseases (chronic bronchitis, emphysema, pneumonia, and tuberculosis) in the development of lung cancer, the authors conducted a pooled analysis of studies in the International Lung Cancer Consortium. Seventeen studies including 24,607 cases and 81,829 controls (noncases), mainly conducted in Europe and North America, were included (1984–2011). Using self-reported data on previous diagnoses of lung diseases, the authors derived study-specific effect estimates by means of logistic regression models or Cox proportional hazards models adjusted for age, sex, and cumulative tobacco smoking. Estimates were pooled using random-effects models. Analyses stratified by smoking status and histology were also conducted. A history of emphysema conferred a 2.44-fold increased risk of lung cancer (95% confidence interval (CI): 1.64, 3.62 (16 studies)). A history of chronic bronchitis conferred a relative risk of 1.47 (95% CI: 1.29, 1.68 (13 studies)). Tuberculosis (relative risk = 1.48, 95% CI: 1.17, 1.87 (16 studies)) and pneumonia (relative risk = 1.57, 95% CI: 1.22, 2.01 (12 studies)) were also associated with lung cancer risk. Among never smokers, elevated risks were observed for emphysema, pneumonia, and tuberculosis. These results suggest that previous lung diseases influence lung cancer risk independently of tobacco use and that these diseases are important for assessing individual risk.
bronchitis; chronic; emphysema; lung diseases; lung neoplasms; meta-analysis; pneumonia; pulmonary disease; chronic obstructive; tuberculosis
Social support is an important resource for communities experiencing disasters. However, a disaster's nature (rapid- versus slow-onset, natural versus technological) may influence community-level responses. Disaster research on social support focuses primarily on rapid-onset natural disasters and, to a lesser extent, rapid-onset technological disasters. Little research has addressed slow-onset disasters. This study explores social support processes in Libby, MT, a community experiencing a “slow-motion technological disaster” due to widespread amphibole asbestos exposure. A comprehensive social support coding system was applied to focus-group and in-depth-interview transcripts. Results reveal that, although the community has a history of normative supportiveness during community and individual crises, that norm has been violated in the asbestos disaster context. Results are interpreted as a failure to achieve an “emergent altruistic community.” Specifically, community-level conflict appears to interfere with previously established social support patterns. The observed phenomenon can be understood as the deterioration of a previously supportive community.
Social support; Slow-motion technological disaster; Altruistic community; Conflict
The link between lung cancer and chronic obstructive lung diseases (COPD) has not been well studied in women even though lung cancer and COPD account for significant and growing morbidity and mortality among women.
We evaluated the relationship between COPD and non-small cell lung cancer (NSCLC) in a population-based case-control study of women and constructed a time course of chronic lung diseases in relation to onset of lung cancer. Five hundred sixty-two women aged 18–74, diagnosed with NSCLC and 564 population-based controls matched on race and age participated. Multivariable unconditional logistic regression models were used to estimate risk associated with a history of COPD, chronic bronchitis or emphysema.
Lung cancer risk increased significantly for white women with a history of COPD (OR=1.85; 95% CI 1.21–2.81), but this was not seen in African American women. Risk associated with a history of chronic bronchitis was strongest when diagnosed at age 25 or earlier (OR=2.35, 95% CI 1.17–4.72); emphysema diagnosed within nine years of lung cancer was also associated with substantial risk (OR=6.36, 95% CI 2.36–17.13). Race, pack-years of smoking, exposure to environmental tobacco smoke as an adult, childhood asthma and exposure to asbestos were associated with a history of COPD among lung cancer cases.
In women, COPD is associated with risk of lung cancer differentially by race. Untangling whether COPD is in the causal pathway or simply shares risk factors will require future studies to focus on specific COPD features while exploring underlying genetic susceptibility to these diseases.
Prior studies indicate that use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAID) is associated with a decreased risk of non-small cell lung cancer (NSCLC); however, results have been contradictory in part because of variation in study design. Few studies have examined the use of aspirin or other NSAIDs on risk of NSCLC in women.
Through a case-control study of African American and Caucasian women with and without NSCLC, we examined the relationship between use of aspirin, NSAIDs, and acetaminophen and risk of NSCLC. Risk was estimated by calculating odds ratios and 95% confidence intervals for ever/never use, duration of use, and duration of use category (never, 1–5 years, >5 years) after adjusting for major risk factors for lung cancer. Risk estimates were stratified by race, age, smoking history, and body mass index.
Ever use of adult-strength aspirin was associated with a significant reduction in risk of NSCLC (odds ratio, 0.66; 95% confidence interval, 0.46–0.94). Additionally, there was a significant trend toward a reduced risk of NSCLC in adult-strength aspirin users with increasing duration of use (Ptrend = 0.02). In stratified analyses, aspirin use was associated with a significantly reduced risk of lung cancer among Caucasians and 55- to 64-year-olds. Baby aspirin and NSAID use was associated with a significant reduction in risk of NSCLC only among 65- to 74-year-olds.
Our results suggest that long-term use of adult-strength aspirin may reduce the risk of NSCLC in women.
Studies on the relationships between inflammatory pathway genes and lung cancer risk have not included African-Americans and have only included a handful of genes. In a population-based case-control study on 198 African-American and 744 Caucasian women, we examined the association between 70 cytokine and cytokine receptor single-nucleotide polymorphisms (SNPs) and risk of non–small cell lung cancer (NSCLC). Unconditional logistic regression was used to estimate odds ratios and 95% confidence intervals in a dominant model adjusting for major risk factors for lung cancer. Separate analyses were conducted by race and by smoking history and history of chronic obstructive pulmonary disease among Caucasians. Random forest analysis was conducted by race. On logistic regression analysis, IL6 (interleukin 6), IL7R, IL15, TNF (tumor necrosis factor), and IL10 SNP were associated with risk of non–small cell lung cancer among African-Americans; IL7R and IL10 SNPs were also associated with risk of lung cancer among Caucasians. Although random forest analysis showed IL7R and IL10 SNPs as being associated with risk for lung cancer among African-Americans, it also identified TNFRSF10A SNP as an important predictor. On random forest analysis, an IL1A SNP was identified as an important predictor of lung cancer among Caucasian women. Inflammatory SNPs differentially predicted risk for NSCLC according to race, as well as based on smoking history and history of chronic obstructive pulmonary disease among Caucasian women. Pathway analysis results are presented. Inflammatory pathway genotypes may serve to define a high risk group; further exploration of these genes in minority populations is warranted.
Background and Methods
Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analyzed. Unconditional logistic regression models and generalized estimating equations were used to estimate odds ratios and 95% confidence intervals.
Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in risk of lung cancer, after adjustment for smoking and other potential confounders(95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (OR=1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR=1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR=1.44, 95% CI: 1.07, 1.93), after adjustment.
The increased risk among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those associated with cigarette smoking. While the role of genetic variation in the etiology of lung cancer remains to be fully characterized, family history assessment is immediately available and those with a positive history represent a higher risk group.
We aimed at extending the natural and orthogonal interaction (NOIA) framework, developed for modeling gene-gene interactions in the analysis of quantitative traits, to allow for reduced genetic models, dichotomous traits, and gene-environment interactions. We evaluate the performance of the NOIA statistical models using simulated data and lung cancer data.
The NOIA statistical models are developed for the additive, dominant, recessive genetic models, and a binary environmental exposure. Using the Kronecker product rule, a NOIA statistical model is built to model gene-environment interactions. By treating the genotypic values as the logarithm of odds, the NOIA statistical models are extended to the analysis of case-control data.
Our simulations showed that power for testing associations while allowing for interaction using the statistical model is much higher than using functional models for most of the scenarios we simulated. When applied to the lung cancer data, much smaller P-values were obtained using the NOIA statistical model for either the main effects or the SNP-smoking interactions for some of the SNPs tested.
The NOIA statistical models are usually more powerful than the functional models in detecting main effects and interaction effects for both quantitative traits and binary traits.
Statistical power; Genetic association studies; Case-control association analysis; Gene-environment interaction; Environmental risk factor; Association mapping; Orthogonal modeling
Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968.
To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking.
Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy.
Uniform statistical analysis scripts were run locally. Starting with 94 050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD ≤10) with age-at-onset information, reducing the sample size to 33 348. Each study was stratified into early-onset smokers (age at onset ≤16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum.
Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR]=1.45; 95% CI, 1.36–1.55; n=13 843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21–1.33, n = 19 505) (P = .01).
These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
Genome-wide sequencing identified heterozygous, constitutional, Ataxia telangiectaisa mutated (ATM) gene mutations in two kindreds with familial pancreatic cancer. Mutations segregated with disease in both kindreds and tumor analysis demonstrated LOH of the wildtype allele. Sequence analysis of an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene, while no deleterious mutations were identified in 190 spouse controls (p=0.046). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition.
ATM; predisposition; familial; pancreas; cancer