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1.  Clinical Characteristics of Breast Cancers in African-American Women with Benign Breast Disease: A Comparison to the Surveillance, Epidemiology, and End Results Program 
The breast journal  2014;20(6):571-577.
Benign breast disease (BBD) is a very common condition, diagnosed in approximately half of all American women throughout their lifecourse. White women with BBD are known to be at substantially increased risk of subsequent breast cancer; however, nothing is known about breast cancer characteristics that develop after a BBD diagnosis in African-American women. Here, we compared 109 breast cancers that developed in a population of African-American women with a history of BBD to 10,601 breast cancers that developed in a general population of African-American women whose cancers were recorded by the Metropolitan Detroit Cancer Surveillance System (MDCSS population). Demographic and clinical characteristics of the BBD population were compared to the MDCSS population, using chi-squared tests, Fisher's exact tests, t-tests, and Wilcoxon tests where appropriate. Kaplan–Meier curves and Cox regression models were used to examine survival. Women in the BBD population were diagnosed with lower grade (p = 0.02), earlier stage cancers (p = 0.003) that were more likely to be hormone receptor-positive (p = 0.03) compared to the general metropolitan Detroit African-American population. In situ cancers were more common among women in the BBD cohort (36.7%) compared to the MDCSS population (22.1%, p < 0.001). Overall, women in the BBD population were less likely to die from breast cancer after 10 years of follow-up (p = 0.05), but this association was not seen when analyses were limited to invasive breast cancers. These results suggest that breast cancers occurring after a BBD diagnosis may have more favorable clinical parameters, but the majority of cancers are still invasive, with survival rates similar to the general African-American population.
doi:10.1111/tbj.12331
PMCID: PMC4201874  PMID: 25200244
African-American; benign breast disease; breast cancer; risk; survival
2.  Benign breast disease and the risk of subsequent breast cancer in African American women 
Benign breast disease (BBD) is an established risk factor for breast cancer among Caucasian women, but less is known about BBD in African American (AA) women. As AA women suffer from disproportionate mortality due to breast cancer, special focus on pathological characteristics that may influence disease risk is warranted.
Benign breast biopsies from AA women were identified by the University Pathology Group in Detroit, Michigan. AA women age 20 to 84 who underwent a breast biopsy from 1997 to 2000 were eligible for the study. Subsequent breast cancers were identified through a linkage with the Detroit SEER program. The first biopsy was reviewed by the pathologist, and lesions were classified following Dupont and Page criteria along with involution and other histologic features. Logistic regression was used to estimate the risk of developing a subsequent breast cancer with the histologic characteristics of BBD.
1,406 BBD biopsies from AA women were included in this study with a median follow-up of 10.1 years. The majority (68%) showed non-proliferative disease, 29% had proliferative disease without atypia, and 3% had proliferative disease with atypia. Subsequent incident breast cancers occurred in 55 women (3.9%). Women whose biopsies showed proliferative disease with atypia were over three-fold more likely to develop breast cancer as women who had non-proliferative disease (RR 3.29, 95% C.I. 1.21-8.93).
Better characterization of the risk of breast cancer among women with BBD, considering both ethnicity and detailed molecular findings, can lead to better surveillance, earlier diagnosis, and, potentially, improved survival.
doi:10.1158/1940-6207.CAPR-12-0175
PMCID: PMC3518609  PMID: 23087047
3.  Racial differences in oncogene mutations detected in early stage, low grade endometrial cancers 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/IGC.0b013e31826b1110
PMCID: PMC3512561  PMID: 23013731
4.  Cigarette smoking and renal cell carcinoma risk among black and white Americans: effect modification by hypertension and obesity 
Introduction
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.
Methods
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.
Results
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.
Conclusion
Our observation that smoking is associated with RCC only in non-obese individuals and those with no history of hypertension are novel findings
Impact
The complex relationships between RCC, smoking, hypertension and obesity require additional confirmation.
doi:10.1158/1055-9965.EPI-11-1109
PMCID: PMC3348421  PMID: 22426145
Renal Cell Carcinoma; Cigarette Smoking; Hypertension; Body Mass Index; Race/Ethnicity
5.  Re-contacting participants for inclusion in the database of Genotypes and Phenotypes (dbGaP): Findings from three case-control studies of lung cancer 
Genome Medicine  2014;6(7):54.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/s13073-014-0054-x
PMCID: PMC4165358  PMID: 25228924
6.  An investigation of risk factors for renal cell carcinoma by histologic subtype in two case-control studies 
To investigate whether renal cell carcinoma (RCC) histologic subtypes possess different etiologies, we conducted analyses of established RCC risk factors by subtype (clear cell, papillary, chromophobe) in two case-control studies conducted in the United States (1,217 cases, 1,235 controls) and Europe (1,097 cases, 1,476 controls). Histology was ascertained for 706 U.S. cases (58% of total) and 917 European cases (84%) through a central slide review conducted by a single pathologist. For the remaining cases, histology was abstracted from the original diagnostic pathology report. Case-only analyses were performed to compute odds ratios (ORs) and 95% confidence intervals (CI) summarizing subtype differences by age, sex, and race. Case-control analyses were performed to compute subtype-specific ORs for other risk factors using polytomous regression. In case-only analyses, papillary cases (N=237) were older (OR=1.2, 95% CI=1.1–1.4 per 10-year increase), less likely to be female (OR=0.5, 95 % CI=0.4- 0.8) and more likely to be black (OR=2.6, 95% CI=1.8–3.9) compared to clear cell cases (N=1,524). In case-control analyses, BMI was associated with clear cell (OR=1.2, 95% CI=1.1–1.3 per 5kg/m2 increase) and chromophobe RCC (N=80; OR=1.2, 95% CI=1.1- 1.4), but not papillary RCC (OR=1.1, 95% CI=1.0–1.2; test vs. clear cell, P=0.006). No subtype differences were observed for associations with smoking, hypertension or family history of kidney cancer. Our findings support the existence of distinct age, sex and racial distributions for RCC subtypes, and suggest that the obesity-RCC association differs by histology.
doi:10.1002/ijc.27934
PMCID: PMC3717609  PMID: 23150424
Renal cell carcinoma; histology; case-control studies; body mass index
7.  Apoptosis-Related Single Nucleotide Polymorphisms and the Risk of Non-Small Cell Lung Cancer in Women 
Journal of cancer therapeutics & research  2014;3(1):10.7243/2049-7962-3-1.
Background
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 African-American women.
Methods
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 education.
Results
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 African-Americans.
Conclusion
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.
doi:10.7243/2049-7962-3-1
PMCID: PMC4002173  PMID: 24790730
non-small cell lung cancer (NSCLC); single nucleotide polymorphisms; apoptosis; females; APAF-1; CD40; ATM; TNF; TP63
8.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia 
Background
Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
Methods
We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.
Results
The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.
Conclusions
Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
doi:10.1093/jnci/dju061
PMCID: PMC3982896  PMID: 24681604
9.  Trends in the Utilization of Adjuvant Vaginal Cuff Brachytherapy and/or External Beam Radiation Treatment in Stage I and II Endometrial Cancer: A Surveillance, Epidemiology, and End-Results Study 
International journal of radiation oncology, biology, physics  2011;83(1):10.1016/j.ijrobp.2011.05.052.
Purpose
The optimal adjuvant radiation treatment for endometrial carcinoma (EC) remains controversial. Adjuvant vaginal cuff brachytherapy (VB) has emerged as an increasingly common treatment modality. However, the time trends for using VB, external beam radiation therapy (EBRT), or combined therapy (VB+EBRT) have not been well characterized. We therefore examined the utilization trends of VB, EBRT, and VB+EBRT for adjuvant RT in International Federation of Gynecologic Oncology (FIGO) stage I and II EC over time.
Methods and Materials
We evaluated treatment patterns for 48,122 patients with EC diagnosed between January 1995 and December 2005, using the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) public use database. Chi-squared tests were used to assess differences by radiation type (VB, EBRT, and VB+EBRT) and various demographic and clinical variables.
Results
Analyses were limited to 9,815 patients (20.4%) with EC who met the inclusion criteria. Among women who received adjuvant RT, the proportion receiving VB increased yearly (12.9% in 1995 compared to 32.8% in 2005 (p < 0.0001). The increasing use of VB was proportional to the decreasing use of EBRT (56.1% in 1995 to 45.8% in 2005; p < 0.0001) and VB+EBRT (31.0% in 1995 to 21.4% in 2005; p < 0.001).
Conclusions
This population-based report demonstrates an increasing trend in the use of VB in the adjuvant setting after hysterectomy for treatment of women with FIGO stage I–II EC. VB alone appears to be replacing pelvic EBRT and VB+EBRT therapy in the management of stage I–II EC.
doi:10.1016/j.ijrobp.2011.05.052
PMCID: PMC3865892  PMID: 22014953
Adjuvant; Brachytherapy; Radiation treatment; SEER; Trends; Uterine carcinoma
10.  Parameters for individualizing systemic therapy in non-small cell lung cancer 
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.
doi:10.1016/j.drup.2010.10.001
PMCID: PMC3865930  PMID: 21051275
Lung cancer; ERCC1; RRM1; TS; EGFR; EML4-ALK; Crizotinib; Bevacizumab
11.  Meta- and Pooled Analysis of GSTP1 Polymorphism and Lung Cancer: A HuGE-GSEC Review 
American Journal of Epidemiology  2009;169(7):802-814.
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.
doi:10.1093/aje/kwn417
PMCID: PMC2727222  PMID: 19240225
Asian continental ancestry group; epidemiology; glutathione S-transferase pi; GSTP1; lung neoplasms; smoking
12.  Fibroblast Growth Factor Receptor 1 Amplification in Non-Small Cell Lung Cancer by Quantitative Real-Time PCR 
PLoS ONE  2013;8(11):e79820.
Introduction
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.
Results
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.
Discussion
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.
doi:10.1371/journal.pone.0079820
PMCID: PMC3821849  PMID: 24255716
13.  Previous Lung Diseases and Lung Cancer Risk: A Pooled Analysis From the International Lung Cancer Consortium 
American Journal of Epidemiology  2012;176(7):573-585.
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.
doi:10.1093/aje/kws151
PMCID: PMC3530374  PMID: 22986146
bronchitis; chronic; emphysema; lung diseases; lung neoplasms; meta-analysis; pneumonia; pulmonary disease; chronic obstructive; tuberculosis
14.  Regular Adult Aspirin Use Decreases the Risk of Non-Small Cell Lung Cancer among Women 
Background
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.
Methods
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.
Results
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.
Conclusion
Our results suggest that long-term use of adult-strength aspirin may reduce the risk of NSCLC in women.
doi:10.1158/1055-9965.EPI-07-0517
PMCID: PMC3771076  PMID: 18187393
15.  Cytokine and Cytokine Receptor Single-Nucleotide Polymorphisms Predict Risk for Non–Small Cell Lung Cancer among 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.
doi:10.1158/1055-9965.EPI-08-0962
PMCID: PMC3771080  PMID: 19505916
16.  Racial Differences in the Association Between SNPs on 15q25.1, Smoking Behavior, and Risk of Non-small Cell Lung Cancer 
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/JTO.0b013e3181b244ef
PMCID: PMC3768000  PMID: 19641473
Non-small cell lung cancer; Smoking; SNPs
17.  A Comparison of Logistic Regression, Logic Regression, Classification Tree, and Random Forests to Identify Effective Gene-Gene and Gene-Environmental Interactions 
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.
PMCID: PMC3686280  PMID: 23795347
SNP interactions; Logistic regression; Classification tree; Logic regression; Random Forests; Cross-validation error; Area under the Curve
18.  ATM mutations in hereditary pancreatic cancer patients 
Cancer discovery  2011;2(1):41-46.
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.
doi:10.1158/2159-8290.CD-11-0194
PMCID: PMC3676748  PMID: 22585167
ATM; predisposition; familial; pancreas; cancer
19.  Asthma and lung cancer risk: a systematic investigation by the International Lung Cancer Consortium 
Carcinogenesis  2011;33(3):587-597.
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.
doi:10.1093/carcin/bgr307
PMCID: PMC3291861  PMID: 22198214
20.  The relationship between COPD and lung cancer in African American patients 
Clinical lung cancer  2011;13(2):149-156.
Rationale
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.
Objective
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1016/j.cllc.2011.09.006
PMCID: PMC3422020  PMID: 22129972
21.  Admixture mapping of lung cancer in 1812 African-Americans 
Carcinogenesis  2010;32(3):312-317.
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.
doi:10.1093/carcin/bgq252
PMCID: PMC3047238  PMID: 21115650
22.  Frequency and type of epidermal growth factor receptor mutations in African Americans with non-small cell lung cancer 
Background
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.
Methods
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).
Results
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).
Conclusion
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.
doi:10.1097/JTO.0b013e31820a0ec0
PMCID: PMC3057407  PMID: 21317742
EGFR mutation; race; African American; lung cancer
23.  HNF1B and Endometrial Cancer Risk: Results from the PAGE study 
PLoS ONE  2012;7(1):e30390.
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.
doi:10.1371/journal.pone.0030390
PMCID: PMC3267708  PMID: 22299039
24.  Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case–control studies in the International Lung Cancer Consortium (ILCCO) 
Cancer Causes & Control  2010;22(1):73-79.
Background
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.
Methods
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.
Results
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).
Conclusions
This analysis provides a precise estimate of the risk of BAC for tobacco smoking.
doi:10.1007/s10552-010-9676-5
PMCID: PMC3002160  PMID: 21072579
Lung cancer; Bronchioloalveolar carcinoma; Tobacco smoking
25.  Cytokine SNPs: Comparison of Allele Frequencies by Race & Implications for Future Studies 
Cytokine  2009;46(2):236-244.
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.
doi:10.1016/j.cyto.2009.02.003
PMCID: PMC2742911  PMID: 19356949
Cytokines; SNPs; Racial Differences; Women

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