To describe the pattern and frequency of oncogene mutations in white and African American (AA) women with endometrial cancer, and to determine if racial differences in oncogene mutations exist among women with pathologically similar tumors.
Endometrial cancer patients from a large, urban hospital were identified through medical records, and representative formalin fixed paraffin embedded tumor blocks were retrieved. The study sample included 150 patients (84 AA) who underwent total abdominal hysterectomy for endometrial cancer. The Sequenom MassARRAY system and the OncoCarta Assay v1.0 (Sequenom), were employed to test for 238 mutations in 19 common oncogenes. Chi-square tests and Fisher’s exact tests were used to assess differences in distribution of variables by race and oncogene mutation status.
There were 20 mutations identified in 2 oncogenes (PIK3CA and KRAS) in tumors from 19 women (12.7%). The majority of mutations were found in PIK3CA (16/20). Thirteen percent of endometroid tumors harbored mutations (11 PIK3CA and 2 KRAS), as did 29% of the Malignant Mixed Mullerian tumors (3 PIK3CA and 1 KRAS). There were no observed mutations in serous, clear cell, or mucinous tumor types. Among low grade endometrioid cancers, tumors from AA patients were significantly associated with harboring either a KRAS or PIK3CA mutation (p=0.04), with 7 PIK3CA mutations and all 4 KRAS mutations identified in AA women.
This study provides preliminary evidence that oncogene mutation frequency of some subtypes of histologically similar endometrial carcinoma differ by race. Additional studies are needed to further explore this phenomenon in patients with endometrial carcinoma.
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
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.
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
Genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) that are associated with a variety of common human diseases. Due to the weak marginal effect of most disease-associated SNPs, attention has recently turned to evaluating the combined effect of multiple disease-associated SNPs on the risk of disease. Several recent multigenic studies show potential evidence of applying multigenic approaches in association studies of various diseases including lung cancer. But the question remains as to the best methodology to analyze single nucleotide polymorphisms in multiple genes. In this work, we consider four methods—logistic regression, logic regression, classification tree, and random forests—to compare results for identifying important genes or gene-gene and gene-environmental interactions. To evaluate the performance of four methods, the cross-validation misclassification error and areas under the curves are provided. We performed a simulation study and applied them to the data from a large-scale, population-based, case-control study.
SNP interactions; Logistic regression; Classification tree; Logic regression; Random Forests; Cross-validation error; Area under the Curve
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
Incidence of kidney cancer has been increasing over the past three decades, with more rapid increases and higher incidence rates among blacks than whites in the United States. An association between cigarette smoking and renal cell carcinoma (RCC), the most common form of kidney cancer, has been reported for whites, but the association in blacks is less clear.
The association between smoking and RCC was examined in 1,217 incident cases and 1,235 population controls frequency-matched on age, race, gender and study site in the Kidney Cancer Study in Detroit, MI and Chicago, IL.
In white individuals, increasing duration and number of pack years of were both associated with increased risk of RCC after adjusting for age, gender, education, study site, body mass index (BMI) and history of hypertension (p-trend=0.0002 and p-trend=0.002, respectively). Among black individuals, RCC risk increased with duration of smoking (p- trend=0.02), but not other measures. Compared to current smokers, RCC risk decreased with increasing years of smoking cessation among both whites and blacks (p- trend=0.01 and 0.02, respectively). When examining risk according to hypertension history, associations between smoking and RCC risk were observed only among individuals who reported never having been diagnosed with hypertension. Similarly, cigarette smoking was associated with increased risk of RCC among non-obese individuals, but not among those with BMI≥30 kg/m2.
Our observation that smoking is associated with RCC only in non-obese individuals and those with no history of hypertension are novel findings
The complex relationships between RCC, smoking, hypertension and obesity require additional confirmation.
Renal Cell Carcinoma; Cigarette Smoking; Hypertension; Body Mass Index; Race/Ethnicity
Airflow obstruction and/or emphysema have been associated with lung cancer risk, however this relationship and the joint occurrence of these conditions are not well studied in the African American population.
Describe the prevalence of airflow obstruction and/or emphysema in African Americans with lung cancer and evaluate their impact on the management and outcome of lung cancer.
Medical records were reviewed for 114 African Americans who had participated in population-based case-control studies of lung cancer and who sought medical care at the Karmanos Cancer Center in Detroit, Michigan. The medical records of these patients were reviewed for demographics, type and stage of lung cancer, spirometry, treatment and outcome. The chest CT scans around the time of the diagnosis of lung cancer were reviewed by a radiologist for evidence of emphysema. COPD was diagnosed when there were changes consistent with emphysema on CT scan and/or airflow obstruction by spirometry.
There were no differences by sex for age at lung cancer diagnosis (p=0.78) and tumor histology (p=0.43). Men were more likely to present at a later stage of lung cancer diagnosis compared to women (p=0.04) and women were more likely to have surgery than men (p=0.03). Overall, 94% of men and 78% of women in this population had spirometry and/or CT evidence of COPD. Men were somewhat more likely to have COPD diagnosed by either CT or spirometry than women (p=0.06), but the GOLD Classification scores did not differ by gender among those with spirometry-diagnosed COPD (p=0.34). Seventy eight percent of individuals who did not report a previous diagnosis of COPD had clinical evidence of COPD, whereas 94% of individuals who reported a previous diagnosis of COPD also had clinical evidence of COPD (p=0.03). Among individuals who had both spirometry and CT data available, 29% had CT evidence of emphysema but normal spirometry. No differences in COPD diagnosis (p=0.82) or emphysema diagnosis (p=0.51) were noted by tumor histology. Stage at diagnosis also did not differ by COPD or emphysema diagnosis (p=0.30 and p=0.06, respectively), nor did treatment modality (p=0.54 and p=0.10, respectively). Lung cancer patients with COPD diagnosed either via spirometry or CT did not show an increased risk of death compared to lung cancer patients without COPD after adjusting for age at diagnosis, gender and stage (HR=1.31 95% CI: 0.68-2.53).
There is a high incidence of COPD, emphysema in particular, in a selected group of African American patients with lung cancer. A significant number of these patients were not aware that they had COPD. There was no significant difference in the outcome of lung cancer in relation to the presence or absence of COPD.
Lung cancer continues to be the leading cause of cancer death in the USA and the best example of a cancer with undisputed evidence of environmental risk. However, a genetic contribution to lung cancer has also been demonstrated by studies of familial aggregation, family-based linkage, candidate gene studies and most recently genome-wide association studies (GWAS). The African-American population has been underrepresented in these genetic studies and has patterns of cigarette use and linkage disequilibrium that differ from patterns in other populations. Therefore, studies in African-Americans can provide complementary data to localize lung cancer susceptibility genes and explore smoking dependence-related genes. We used admixture mapping to further characterize genetic risk of lung cancer in a series of 837 African-American lung cancer cases and 975 African-American controls genotyped at 1344 ancestry informative single-nucleotide polymorphisms. Both case-only and case–control analyses were conducted using ADMIXMAP adjusted for age, sex, pack-years of smoking, family history of lung cancer, history of emphysema and study site. In case-only analyses, excess European ancestry was observed over a wide region on chromosome 1 with the largest excess seen at rs6587361 for non-small-cell lung cancer (NSCLC) (Z-score = −4.33; P = 1.5 × 10−5) and for women with NSCLC (Z-score = −4.82; P = 1.4 × 10−6). Excess African ancestry was also observed on chromosome 3q with a peak Z-score of 3.33 (P = 0.0009) at rs181696 among ever smokers with NSCLC. These results add to the findings from the GWAS in Caucasian populations and suggest novel regions of interest.
Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer predict response to tyrosine kinase inhibitors (TKIs). Mutations occur more commonly in never-smokers and East Asians but there are conflicting reports on the frequency of EGFR mutations in tumors from African Americans.
Tumors from 67 African American and 77 Caucasian participants in previous case-control studies of lung cancer were selected to determine EGFR mutational status. Mutation analysis was performed using the Sequenom mass array analyzer (Sequenom, San Diego, CA).
Overall, 13.9% of the study population carried an EGFR mutation. EGFR mutations occurred in 11.9% of tumors from African Americans compared with 15.6% in Caucasians (p=0.53). All mutations found in African Americans were deletions in exon 19. The majority of mutations were found in non-smokers among both African Americans (7/8) and Caucasians (8/12).
These results indicate that African Americans with non-small cell lung cancer (NSCLC) harbor somatic EGFR mutations at a frequency similar to Caucasians with NSCLC. Thus, clinicians should not use race as a clinical decision parameter for the use of EGFR-TKIs.
EGFR mutation; race; African American; lung cancer
We examined the association between HNF1B variants identified in a recent genome-wide association study and endometrial cancer in two large case-control studies nested in prospective cohorts: the Multiethnic Cohort Study (MEC) and the Women's Health Initiative (WHI) as part of the Population Architecture using Genomics and Epidemiology (PAGE) study. A total of 1,357 incident cases of invasive endometrial cancer and 7,609 controls were included in the analysis (MEC: 426 cases/3,854 controls; WHI: 931cases/3,755 controls). The majority of women in the WHI were European American, while the MEC included sizable numbers of African Americans, Japanese and Latinos. We estimated the odds ratios (ORs) per allele and 95% confidence intervals (CIs) of each SNP using unconditional logistic regression adjusting for age, body mass index, and four principal components of ancestry informative markers. The combined ORs were estimated using fixed effect models. Rs4430796 and rs7501939 were associated with endometrial cancer risk in MEC and WHI with no heterogeneity observed across racial/ethnic groups (P≥0.21) or between studies (P≥0.70). The ORper allele was 0.82 (95% CI: 0.75, 0.89; P = 5.63×10−6) for rs4430796 (G allele) and 0.79 (95% CI: 0.73, 0.87; P = 3.77×10−7) for rs7501939 (A allele). The associations with the risk of Type I and Type II tumors were similar (P≥0.19). Adjustment for additional endometrial cancer risk factors such as parity, oral contraceptive use, menopausal hormone use, and smoking status had little effect on the results. In conclusion, HNF1B SNPs are associated with risk of endometrial cancer and that the associated relative risks are similar for Type I and Type II tumors.
The International Lung Cancer Consortium (ILCCO) was established in 2004, based on the collaboration of research groups leading large molecular epidemiology studies of lung cancer that are ongoing or have been recently completed. This framework offered the opportunity to investigate the role of tobacco smoking in the development of bronchioloalveolar carcinoma (BAC), a rare form of lung cancer.
Our pooled data comprised seven case–control studies from the United States, with detailed information on tobacco smoking and histology, which contributed 799 cases of BAC and 15,859 controls. We estimated the odds ratio of BAC for tobacco smoking, using never smokers as a referent category, after adjustment for age, sex, race, and study center.
The odds ratio of BAC for ever smoking was 2.47 (95% confidence interval [CI] 2.08, 2.93); the risk increased linearly with duration, amount, and cumulative cigarette smoking and persisted long after smoking cessation. The proportion of BAC cases attributable to smoking was 0.47 (95% CI 0.39, 0.54).
This analysis provides a precise estimate of the risk of BAC for tobacco smoking.
Lung cancer; Bronchioloalveolar carcinoma; Tobacco smoking
The role of inflammation is being considered in chronic diseases. Previous studies have examined SNPs in a few key inflammatory genes and have included small numbers of African American participants. Variation in the frequencies of inflammatory pathway SNPs may help to explain racial disparities in disease risk. Through a population-based study of 103 African American and 380 Caucasian unrelated, healthy women, we examined the relationships between race and allele frequencies of 70 cytokine and cytokine receptor SNPs. The associations between genotypic and haplotype frequencies and race were also analyzed. Allelic frequencies for 52 out of the 70 SNPs meeting criteria for analysis differed significantly by race. Of the 32 pro-inflammatory and 20 anti-inflammatory SNPs for which the allele frequencies varied significantly by race, variant allele frequency differences between Caucasians and African Americans ranged between 6%–37% and 7%–53% for pro-inflammatory SNPs and anti-inflammatory SNPs, respectively. Our findings suggest that while allele frequencies do vary by race, racial groups are not simplistically represented by a pro-inflammatory or anti-inflammatory genetic profile. Given the racial variability in allele frequencies in inflammatory gene SNPs, studies examining the association between these SNPs and disease should at least incorporate self-reported race in their analyses.
Cytokines; SNPs; Racial Differences; Women
Because existing risk prediction models for lung cancer were developed in white populations, they may not be appropriate for predicting risk among African-Americans. Therefore, a need exists to construct and validate a risk prediction model for lung cancer that is specific to African-Americans. We analyzed data from 491 African-Americans with lung cancer and 497 matched African-American controls to identify specific risks and incorporate them into a multivariable risk model for lung cancer and estimate the 5-year absolute risk of lung cancer. We performed internal and external validations of the risk model using data on additional cases and controls from the same ongoing multiracial/ethnic lung cancer case-control study from which the model-building data were obtained as well as data from two different lung cancer studies in metropolitan Detroit, respectively. We also compared our African-American model with our previously developed risk prediction model for whites. The final risk model included smoking-related variables [smoking status, pack-years smoked, age at smoking cessation (former smokers), and number of years since smoking cessation (former smokers)], self- reported physician diagnoses of chronic obstructive pulmonary disease or hay fever, and exposures to asbestos or wood dusts. Our risk prediction model for African-Americans exhibited good discrimination [75% (95% confidence interval, 0.67−0.82)] for our internal data and moderate discrimination [63% (95% confidence interval, 0.57−0.69)] for the external data group, which is an improvement over the Spitz model for white subjects. Existing lung cancer prediction models may not be appropriate for predicting risk for African-Americans because (a) they were developed using white populations, (b) level of risk is different for risk factors that African-American share with whites, and (c) unique group-specific risk factors exist for African-Americans. This study developed and validated a risk prediction model for lung cancer that is specific to African-Americans and thus more precise in predicting their risks. These findings highlight the importance of conducting further ethnic-specific analyses of disease risk.
Lung cancer is the most common cancer worldwide. Polymorphisms in genes associated with carcinogen metabolism may modulate risk of disease. Glutathione S-transferase pi (GSTP1) detoxifies polycyclic aromatic hydrocarbons found in cigarette smoke and is the most highly expressed glutathione S-transferase in lung tissue. A polymorphism in the GSTP1 gene, an A-to-G transition in exon 5 (Ile105Val, 313A → 313G), results in lower activity among individuals who carry the valine allele. The authors present a meta- and a pooled analysis of case-control studies that examined the association between this polymorphism in GSTP1 and lung cancer risk (27 studies, 8,322 cases and 8,844 controls and 15 studies, 4,282 cases and 5,032 controls, respectively). Overall, the meta-analysis found no significant association between lung cancer risk and the GSTP1 exon 5 polymorphism. In the pooled analysis, there was an overall association (odds ratio = 1.11, 95% confidence interval: 1.03, 1.21) between lung cancer and carriage of the GSTP1 Val/Val or Ile/Val genotype compared with those carrying the Ile/Ile genotype. Increased risk varied by histologic type in Asians. There appears to be evidence for interaction between amount of smoking, the GSTP1 exon 5 polymorphism, and risk of lung cancer in whites.
Asian continental ancestry group; epidemiology; glutathione S-transferase pi; GSTP1; lung neoplasms; smoking
To explore the potential role for estrogen in lung cancer susceptibility, candidate single-nucleotide polymorphism (SNPs) in tobacco and estrogen metabolism genes were evaluated. Population-based cases (n = 504) included women aged 18–74, diagnosed with NSCLC in metropolitan Detroit between November 2001 and October 2005. Population-based controls (n = 527) were identified through random digit dialing and matched on race and age. Eleven SNPs in 10 different genes were examined in relation to risk: CYP1A1 Msp1, CYP1A1 Ile462Val, CYP1B1 Leu432Val, CYP17, CYP19A1, XRCC1 Gln399Arg, COMT Val158Met, NQO1 Pro187Ser, GSTM1, GSTT1 and GSTP1 Ile105Val. Lung cancer risk associated with individual SNPs was seen for GSTP1 [A allele; odds ratio (OR) = 1.85; 95% confidence interval (CI), 1.04–3.27] and XRCC1 (A/A genotype; OR = 1.68; 95% CI, 1.01–2.79) in white women and CYP1B1 (G allele; OR = 11.1; 95% CI, 1.18–104) in black women smokers. White women smokers carrying two risk genotypes at the following loci were at increased risk of lung cancer compared with individuals not carrying risk alleles at these loci: CYP17 and GSTM1, COMT and GSTM1, CYP17 and GSTT1, XRCC1 and GSTP1, CYP1B1 and XRCC1 and COMT and XRCC1. The most parsimonious model of lung cancer risk in white smoking women included age, family history of lung cancer, history of chronic lung disease, pack-years, body mass index, XRCC1 A/A genotype, GSTM1 null and COMT A/G or G/G genotype. These findings support the need for continued study of estrogen in relation to lung cancer risk. Polymorphisms in the tobacco metabolism, estrogen metabolism and DNA repair pathways will be useful in developing more predictive models of individual risk.
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.
In a population-based case-control study, we explored the associations between 42 polymorphisms in seven genes in this region and non-small cell lung cancer (NSCLC) risk among Caucasian (364 cases; 380 controls) and African American (95 cases; 103 controls) women. Two TERT region SNPs, rs2075786 and rs2853677, conferred an increased risk of developing NSCLC, especially among African American women, and TERT-rs2735940 was associated with a decreased risk of lung cancer among African Americans. Five of the 20 GHR polymorphisms and SEPP1-rs6413428 were associated with a marginally increased risk of NSCLC among Caucasians. Random forest analysis reinforced the importance of GHR among Caucasians and identified AMACR, TERT, and GHR among African Americans, which were also significant using gene-based risk scores. Smoking-SNP interactions were explored, and haplotypes in TERT and GHR associated with NSCLC risk were identified. The roles of TERT, GHR, AMACR and SEPP1 genes in lung carcinogenesis warrant further exploration.
Previous studies suggest that cyclooxygenase-2 (COX-2) expression may predict survival among patients with non-small cell lung cancer. COX-2 may interact with epidermal growth factor receptor (EGFR), suggesting that combined COX-2/EGFR expression may provide predictive value. The extent to which their independent or combined expression is associated with prognosis in women with adenocarcinoma of the lung is unknown. In the present study, we examined relationships between COX-2 expression (n = 238), EGFR expression (n = 158) and dual COX-2/EGFR expression (n = 157) and survival among women with adenocarcinoma of the lung. Overall survival was estimated by constructing Cox proportional hazards models adjusting for other significant variables and stratifying by stage at diagnosis and race. Clinical or demographic parameters were not associated with either COX-2 or EGFR expression. Patients with COX-2-positive tumors tended to have poorer prognosis than did patients with COX-2-negative tumors [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.01–2.78]. African-Americans with COX-2-positive tumors had a statistically non-significant higher risk of death than African-Americans with COX-2-negative tumors (HR 5.58, 95% CI 0.64–48.37). No association between COX-2 expression and survival was observed among Caucasians (HR 1.29, 95% CI 0.72–2.30). EGFR expression was associated with a 44% reduction in the risk of death (HR 0.56, 95% CI 0.32–0.98). COX-2−/EGFR+ tumor expression, but not COX-2+/EGFR+ tumor expression, was associated with survival when compared with other combined expression results. In conclusion, COX-2 and EGFR expression, but not combined COX-2+/EGFR+ expression, independently predict survival of women with adenocarcinoma of the lung.
Inherited predisposition to pancreas cancer accounts for approximately 10% of cases. Familial aggregation may be influenced by shared environmental factors and shared genes. We evaluate whether a family history of pancreas cancer is a risk factor for ten specified cancers in first-degree relatives: bladder, breast, colon, head & neck, lung, lymphoma, melanoma, ovary, pancreas and prostate.
Risk factor data and cancer family history were obtained for 1816 first-degree relatives of pancreas cancer case probands (n=247) and 3157 first-degree relatives of control probands (n=420). Unconditional logistic regression models using generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals of having a first-degree relative a specified cancer.
A family history of pancreas cancer was associated with a doubled risk of lymphoma (OR = 2.83, 95% CI = 1.02–7.86) and ovarian cancer (OR = 2.25, 95% CI = 0.77–6.60) among relatives after adjustment. Relatives with a family history of early-onset pancreas cancer in a proband had a 7-fold increased risk of lymphoma (OR = 7.31, 95% CI = 1.45 – 36.7). Relatives who ever smoked and had a family history of pancreas cancer had a 5-fold increased risk of ovarian cancer (OR = 4.89, 95% CI = 1.16–20.6).
Family history assessment of cancer risk should include all cancers. Assessment of other known and suspected risk factors in relatives will improve risk evaluation. As screening and surveillance methods are developed, identifying those at highest risk is crucial for a successful screening program.
pancreas cancer; lymphoma; ovarian cancer; family history of pancreas cancer; smoking; young age at cancer diagnosis; genetic risk
Asthma has been hypothesized to be associated with lung cancer (LC) risk. We conducted a pooled analysis of 16 studies in the International Lung Cancer Consortium (ILCCO) to quantitatively assess this association and compared the results with 36 previously published studies. In total, information from 585 444 individuals was used. Study-specific measures were combined using random effects models. A meta-regression and subgroup meta-analyses were performed to identify sources of heterogeneity. The overall LC relative risk (RR) associated with asthma was 1.28 [95% confidence intervals (CIs) = 1.16–1.41] but with large heterogeneity (I2 = 73%, P < 0.001) between studies. Among ILCCO studies, an increased risk was found for squamous cell (RR = 1.69, 95%, CI = 1.26–2.26) and for small-cell carcinoma (RR = 1.71, 95% CI = 0.99–2.95) but was weaker for adenocarcinoma (RR = 1.09, 95% CI = 0.88–1.36). The increased LC risk was strongest in the 2 years after asthma diagnosis (RR = 2.13, 95% CI = 1.09–4.17) but subjects diagnosed with asthma over 10 years prior had no or little increased LC risk (RR = 1.10, 95% CI = 0.94–1.30). Because the increased incidence of LC was chiefly observed in small cell and squamous cell lung carcinomas, primarily within 2 years of asthma diagnosis and because the association was weak among never smokers, we conclude that the association may not reflect a causal effect of asthma on the risk of LC.