Assessing a Polygenic Risk Score for Lung Cancer Susceptibility in Non-Hispanic White and Black Populations.

BACKGROUND: Polygenic risk scores (PRS) have become an increasingly popular approach to evaluate cancer susceptibility, but have not adequately represented Black populations in model development. METHODS: We used a previously published lung cancer PRS on the basis of 80 SNPs associated with lung cancer risk in the OncoArray cohort and validated in UK Biobank. The PRS was evaluated for association with lung cancer risk adjusting for age, sex, total pack-years, family history of lung cancer, history of chronic obstructive pulmonary disease, and the top five principal components for genetic ancestry. RESULTS: Among the 80 PRS SNPs included in the score, 14 were significantly associated with lung cancer risk (P < 0.05) in INHALE White participants, while there were no significant SNPs among INHALE Black participants. After adjusting for covariates, the PRS was significantly associated with risk in Whites (continuous score P = 0.007), but not in Blacks (continuous score P = 0.88). The PRS remained a statistically significant predictor of lung cancer risk in Whites ineligible for lung cancer screening under current U.S. Preventive Services Task Force guidelines (P = 0.02). CONCLUSIONS: Using a previously validated PRS, we did find some predictive ability for lung cancer in INHALE White participants beyond traditional risk factors. However, this effect was not observed in Black participants, indicating the need to develop and validate ancestry-specific lung cancer risk models. IMPACT: While a previously published lung cancer PRS was able to stratify White participants into different levels of risk, the model was not predictive in Blacks. Our findings highlight the need to develop and validate ancestry-specific lung cancer risk models.

Evaluation of health behaviors and overall quality of life in younger adult African American cancer survivors.

BACKGROUND: Epidemiological studies of cancer survivors have predominantly focused on non-Hispanic White, elderly patients, despite the observation that African Americans have higher rates of mortality. Therefore, we characterized cancer survivorship in younger African American survivors using the Detroit Research on Cancer Survivors (ROCS) study to assess health behaviors and quality of life. METHODS: Five hundred and seventeen patients diagnosed with any cancer between the ages of 20-49 (mean age: 42 years; SD: 6.7 years) completed a survey to identify important clinical, behavioral, and sociodemographic characteristics, measures of health literacy, and experiences of discrimination. Quality of life outcomes were evaluated in patients using FACT-G, FACT-Cog, and PROMIS® Anxiety and Depression scales. Stepwise linear and logistic regression were used to assess the association between quality of life measures and participant characteristics. RESULTS: The mean FACT-G score was 74.1 (SD: 21.3), while the FACT-Cog was 55.1 (SD: 17.1) (FACT-G range 0-108 with higher scores indicating better function; elderly cancer patient mean: 82.2; FACT-Cog 18-item range 0-72 points with higher scores indicating better perceived cognitive functioning; scores <54 indicating cognitive impairment). In addition, 27.1% and 21.6% of patients had a score indicative of moderate or severe anxiety and depression, respectively. Perceived discrimination and the number of discriminatory events were significantly associated with reductions in three of the four quality of life measures. Health literacy was positively associated with all four health measures, while total comorbidity count was negatively associated with three of the four measures. CONCLUSION: Younger adult African American cancer survivors who report experiencing discrimination and suffer from multiple comorbid conditions have poorer mental and overall health. Understanding the unique clinical and socioeconomic stressors that influence this patient population is essential for reducing health disparities and improving long-term survivorship.

Lung Cancer Screening Criteria and Cardiopulmonary Comorbidities.

Introduction: Lung cancer screening criteria should select candidates with minimal cardiopulmonary comorbidities who are fit for curative lung cancer resection. Methods: We retrospectively analyzed 728 patients with lung cancer for screening eligibility using the U.S. Preventive Services Task Force (USPSTF) 2013 criteria (n = 370). If ineligible for screening, they were further assessed for eligibility using the USPSTF 2021 (n = 121) and National Comprehensive Cancer Network group 2 (NCCN gp 2) (n = 155). Comparisons of cardiopulmonary comorbidities between patients selected by the different lung cancer screening criteria were performed. Excluding missing data, a similar comparison was done between USPSTF 2013 (n = 283) and PLCOm2012 (risk threshold ≥1.51%) (n = 118). Results: Patients eligible for USPSTF 2021 and NCCN gp 2 had lower rates of airflow obstruction (forced expiratory volume in 1 s [FEV1]/forced vital capacity <0.7) compared with those in USPSTF 2013 (55.4% and 56.8% versus 70.5%). Both USPSTF 2021 and NCCN gp 2 groups had less severe airflow obstruction; only 11.6% and 12.9% of patients, respectively, had percent-predicted FEV1 less than 50% versus 20.3% in the USPSTF 2013 group. Comparing USPSTF 2013 and PLCOm2012 revealed no significant differences in age or the rate of airflow obstruction (p = 0.06 and p = 0.09 respectively). Nevertheless, rates of percent-predicted FEV1 less than 50% and diffusing capacity of the lungs for carbon monoxide less than 50% were lower in the PLCOm2012 group compared with those in the USPSTF 2013 group (22.3% versus 10.2% and 32.6% versus 20.0%), respectively. Conclusions: The USPSTF 2021 qualifies an additional group of screening candidates who are healthier with better lung reserve, translating to better surgical candidacy but potentially more overdiagnosis. The PLCOm2012, with its better accuracy in selecting patients at risk of cancer, selects an older group with chronic obstructive pulmonary disease but with good lung reserve and potentially less overdiagnosis.

Comparison Between the 2021 USPSTF Lung Cancer Screening Criteria and Other Lung Cancer Screening Criteria for Racial Disparity in Eligibility.

IMPORTANCE: In 2021, the US Preventive Services Task Force (USPSTF) broadened its age and smoking pack-year requirement for lung cancer screening. OBJECTIVES: To compare the 2021 USPSTF lung cancer screening criteria with other lung cancer screening criteria and evaluate whether the sensitivity and specificity of these criteria differ by race. DESIGN, SETTING, AND PARTICIPANTS: This study included 912 patients with lung cancer and 1457 controls without lung cancer enrolled in an epidemiology study (INHALE [Inflammation, Health, Ancestry, and Lung Epidemiology]) in the Detroit metropolitan area between May 15, 2012, and March 31, 2018. Patients with lung cancer and controls were 21 to 89 years of age; patients with lung cancer who were never smokers and controls who were never smokers were not included in these analyses. Statistical analysis was performed from August 31, 2020, to April 13, 2021. MAIN OUTCOMES AND MEASURES: The study assessed whether patients with lung cancer and controls would have qualified for lung cancer screening using the 2013 USPSTF, 2021 USPSTF, and 2012 modification of the model from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOm2012) screening criteria. Sensitivity was defined as the percentage of patients with lung cancer who qualified for screening, while specificity was defined as the percentage of controls who did not qualify for lung cancer screening. RESULTS: Participants included 912 patients with a lung cancer diagnosis (493 women [54%]; mean [SD] age, 63.7 [9.5] years) and 1457 control participants without lung cancer at enrollment (795 women [55%]; mean [SD] age, 60.4 [9.6] years). With the use of 2021 USPSTF criteria, 590 patients with lung cancer (65%) were eligible for screening compared with 619 patients (68%) per the PLCOm2012 criteria and 445 patients (49%) per the 2013 USPSTF criteria. With the use of 2013 USPSTF criteria, significantly more White patients than African American patients with lung cancer (324 of 625 [52%] vs 121 of 287 [42%]) would have been eligible for screening. This racial disparity was absent when using 2021 USPSTF criteria (408 of 625 [65%] White patients vs 182 of 287 [63%] African American patients) and PLCOm2012 criteria (427 of 625 [68%] White patients vs 192 of 287 [67%] African American patients). The 2013 USPSTF criteria excluded 950 control participants (65%), while the PLCOm2012 criteria excluded 843 control participants (58%), and the 2021 USPSTF criteria excluded 709 control participants (49%). The 2013 USPSTF criteria excluded fewer White control participants than African American control participants (514 of 838 [61%] vs 436 of 619 [70%]). This racial disparity is again absent when using 2021 USPSTF criteria (401 of 838 [48%] White patients vs 308 of 619 [50%] African American patients) and PLCOm2012 guidelines (475 of 838 [57%] White patients vs 368 of 619 [60%] African American patients). CONCLUSIONS AND RELEVANCE: This study suggests that the USPSTF 2021 guideline changes improve on earlier, fixed screening criteria for lung cancer, broadening eligibility and reducing the racial disparity in access to screening.

The impact of the COVID-19 pandemic on African American cancer survivors.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has had profound effects on population health to date. African American cancer survivors are particularly vulnerable to developing severe consequences; therefore, understanding the impact of the virus on this patient population is critical. METHODS: The Detroit Research on Cancer Survivors cohort is a unique effort to understand the determinants of poor outcomes in African American cancer survivors. To date, more than 4500 cancer survivors and nearly 950 primary caregivers have been enrolled; participation includes a survey and the collection of biospecimens, medical records, and tumor tissue. Beginning in the spring of 2020, a supplemental survey focusing on the impact of COVID-19 was offered to enrolled participants. The analysis included 890 survivors. RESULTS: Nearly all survivors (>99%) reported changes in their daily activities in an effort to reduce the risk of infection. More than 40% of the survivors reported some disruption in their access to medical care. A substantial proportion of the survivors (>40%) reported feeling anxious, depressed, and/or isolated during the COVID-19 pandemic. Approximately 40% of the patients reported changes in health behaviors shown to negatively affect survivorship outcomes (physical inactivity, smoking, and alcohol use) as a result of the pandemic. CONCLUSIONS: The influence of the COVID-19 pandemic on African American cancer survivors is substantial: it has affected both their physical and mental health. Coupled with changes in health behaviors, these factors will likely affect outcomes in this high-risk patient population, and this makes further study and interventions necessary to mitigate the long-term impact of the pandemic on cancer outcomes.

Chemotherapy-induced peripheral neuropathy in African American cancer survivors: Risk factors and quality of life outcomes.

BACKGROUND: Epidemiological studies of chemotherapy-induced peripheral neuropathy (CIPN) have predominantly focused on non-Hispanic White patients, despite the observation that African Americans are more likely to experience CIPN. To address this health disparities gap, we sought to identify non-genetic risk factors and comorbidities associated with CIPN in African American cancer survivors using the Detroit Research on Cancer Survivors study. METHODS: Logistic regression was used to evaluate relationships between presence of self-reported CIPN and relevant clinical characteristics in 1045 chemotherapy-treated African American cancer survivors. Linear regression was used to evaluate risk factors for CIPN and quality of life outcomes that reflect physical, social, emotional, and functional domains of health. RESULTS: Patients with CIPN were more likely to report hypertension (OR = 1.28, 95% CI: 0.98-1.67, p = 0.07), hypercholesterolemia (OR = 1.32, 95% CI: 1.001-1.73, p = 0.05), history of depression (OR = 1.62, 95% CI: 1.18-2.25, p = 0.003), and diabetes (OR = 1.33, 95% CI: 0.98-1.82, p = 0.06) after adjustment for age at diagnosis, sex, and cancer site. BMI (OR = 1.02 kg/m2 , 95% CI: 1.006-1.04 kg/m2 , p = 0.008) was also positively associated with CIPN. In addition, CIPN status was significantly associated with quality of life (FACT-G total: ß = -8.60, 95% CI: -10.88, -6.32) p < 0.0001) and mood (PROMIS® Anxiety: ß = 4.18, 95% CI: 2.92-5.45, p < 0.0001; PROMIS® Depression: ß = 2.69, 95% CI: 1.53-3.84, p < 0.0001) after adjustment for age at diagnosis, sex, cancer site, and comorbidities. Neither alcohol consumption (OR = 0.88, 95% CI: 0.68-1.14, p = 0.32) nor tobacco use (ever smoked: OR = 1.04, 95% CI: 0.80-1.35, p = 0.76; currently smoke: OR = 1.28, 95% CI: 0.90-1.82, p = 0.18) was associated with increased CIPN risk. CONCLUSION: Risk factor profiles in African Americans are not entirely consistent with those previously reported for non-Hispanic White patients. Neglecting to understand the correlates of common chemotherapy-induced toxicities for this patient population may further contribute to the health disparities these individuals face in receiving adequate healthcare.

Rare deleterious germline variants and risk of lung cancer.

Recent studies suggest that rare variants exhibit stronger effect sizes and might play a crucial role in the etiology of lung cancers (LC). Whole exome plus targeted sequencing of germline DNA was performed on 1045 LC cases and 885 controls in the discovery set. To unveil the inherited causal variants, we focused on rare and predicted deleterious variants and small indels enriched in cases or controls. Promising candidates were further validated in a series of 26,803 LCs and 555,107 controls. During discovery, we identified 25 rare deleterious variants associated with LC susceptibility, including 13 reported in ClinVar. Of the five validated candidates, we discovered two pathogenic variants in known LC susceptibility loci, ATM p.V2716A (Odds Ratio [OR] 19.55, 95%CI 5.04-75.6) and MPZL2 p.I24M frameshift deletion (OR 3.88, 95%CI 1.71-8.8); and three in novel LC susceptibility genes, POMC c.*28delT at 3' UTR (OR 4.33, 95%CI 2.03-9.24), STAU2 p.N364M frameshift deletion (OR 4.48, 95%CI 1.73-11.55), and MLNR p.Q334V frameshift deletion (OR 2.69, 95%CI 1.33-5.43). The potential cancer-promoting role of selected candidate genes and variants was further supported by endogenous DNA damage assays. Our analyses led to the identification of new rare deleterious variants with LC susceptibility. However, in-depth mechanistic studies are still needed to evaluate the pathogenic effects of these specific alleles.

COPD-dependent effects of genetic variation in key inflammation pathway genes on lung cancer risk.

Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.

Profiling the Mutational Landscape in Known Driver Genes and Novel Genes in African American Non-Small Cell Lung Cancer Patients.

PURPOSE: Identifying novel driver genes and mutations in African American non-small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population. EXPERIMENTAL DESIGN: Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations. RESULTS: Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic. CONCLUSIONS: These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Quantitative Imaging Markers of Lung Function in a Smoking Population Distinguish COPD Subgroups with Differential Lung Cancer Risk.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition with respect to onset, progression, and response to therapy. Incorporating clinical- and imaging-based features to refine COPD phenotypes provides valuable information beyond that obtained from traditional clinical evaluations. We characterized the spectrum of COPD-related phenotypes in a sample of former and current smokers and evaluated how these subgroups differ with respect to sociodemographic characteristics, COPD-related comorbidities, and subsequent risk of lung cancer. METHODS: White (N = 659) and African American (N = 520) male and female participants without lung cancer (controls) in the INHALE study who completed a chest CT scan, interview, and spirometry test were used to define distinct COPD-related subgroups based on hierarchical clustering. Seven variables were used to define clusters: pack years, quit years, FEV1/FVC, % predicted FEV1, and from quantitative CT (qCT) imaging, % emphysema, % air trapping, and mean lung density ratio. Cluster definitions were then applied to INHALE lung cancer cases (N = 576) to evaluate lung cancer risk. RESULTS: Five clusters were identified that differed significantly with respect to sociodemographic (e.g., race, age) and clinical (e.g., BMI, limitations due to breathing difficulties) characteristics. Increased risk of lung cancer was associated with increasingly detrimental lung function clusters (when ordered from most detrimental to least detrimental). CONCLUSIONS: Measures of lung function vary considerably among smokers and are not fully explained by smoking intensity. IMPACT: Combining clinical (spirometry) and radiologic (qCT) measures of COPD defines a spectrum of lung disease that predicts lung cancer risk differentially among patient clusters.

Prognostic modeling of the immune-centric transcriptome reveals interleukin signaling candidates contributing to differential patient outcomes.

Immunotherapy is a promising advancement in the treatment of non-small-cell lung carcinoma (NSCLC), although much of how lung tumors interact with the immune system in the natural course of disease remains unknown. We investigated the impact of the expression of immune-centric genes and pathways in tumors on patient survival to reveal novel candidates for immunotherapeutic research. Tumor transcriptomes and detailed clinical characteristics were obtained from patients with NSCLC who were participants of either the Inflammation, Health and Lung Epidemiology (INHALE) (discovery, N = 280) or The Cancer Genome Atlas (TCGA) Lung (replication, N = 1026) studies. Expressions of 2253 genes derived from 48 major immune pathways were assessed for association with patient prognosis using a multivariable Cox model and pathway effects were assessed with an in-house implementation of the Gene Set Enrichment Analysis (GSEA) algorithm. Prognosis-guided gene and pathway analysis of immune-centric expression in tumors revealed significant survival enrichments across both cohorts. The 'Interleukin Signaling' pathway, containing 430 genes, was found to be statistically and significantly enriched with prognostic signal in both the INHALE (P = 0.008) and TCGA (P = 0.039) datasets. Subsequent leading-edge analysis identified a subset of genes (N = 23) shared between both cohorts, driving the pathway enrichment. Cumulative expression of this leading-edge gene signature was a strong predictor of patient survival [discovery: hazard ratio (HR) = 1.59, P = 3.0 × 10-8; replication: HR = 1.29, P = 7.4 × 10-7]. These data demonstrate the impact of immune-centric expression on patient outcomes in NSCLC. Furthermore, prognostic gene effects were localized to discrete immune pathways, of which Interleukin Signaling had the greatest impact on overall survival and the subset of genes driving these effects have promise for future therapeutic intervention.

Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer.

BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.

Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. METHODS: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than -950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than -856 HU on expiratory scan (HUE). RESULTS: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels <-856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03-1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21-2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD. CONCLUSION: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. IMPACT: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341-7. ©2016 AACR.

Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial.

BACKGROUND: Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma. METHODS: We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445. FINDINGS: Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none). INTERPRETATION: In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors. FUNDING: Novartis and Pfizer.

Whole-exome sequencing reveals genetic variability among lung cancer cases subphenotyped for emphysema.

Lung cancer continues to be a major public health challenge in the United States despite efforts to decrease the prevalence of smoking; outcomes are especially poor for African-American patients compared to other races/ethnicities. Chronic obstructive pulmonary disease (COPD) co-occurs with lung cancer frequently, but not always, suggesting both shared and distinct risk factors for these two diseases. To identify germline genetic variation that distinguishes between lung cancer in the presence and absence of emphysema, we performed whole-exome sequencing on 46 African-American lung cancer cases (23 with and 23 without emphysema frequency matched on age, sex, histology and pack years). Using conditional logistic regression, we found 6305 variants (of 168 150 varying sites) significantly associated with lung cancer subphenotype (P ≤ 0.05). Next, we validated 10 of these variants in an independent set of 612 lung cancer cases (267 with emphysema and 345 without emphysema) from the same population of inference as the sequenced cases. We found one variant that was significantly associated with lung cancer subphenotype in the validation sample. These findings contribute to teasing apart shared genetic factors from independent genetic factors for lung cancer and COPD.

Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study.

Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.

Bladder cancer screening program for a petrochemical cohort with potential exposure to beta-napthylamine.

Approximately 1800 workers in pipe manufacturing plants in the United States may have been exposed to beta-napthlyamnine between 1970 and 1996. Once the chemical was detected, the contaminated additive in the resin was identified and discontinued. A bladder cancer-screening program was initiated in 1999. An annual two-stage screening program was developed to test for microscopic hematuria (stage one) and cytology (stage two), with a urology referral of positive or suspicious cytology. This paper presents the program methodology, cohort enumeration, recruitment, and enrollment strategies, and screening protocol. Enrollment data from the first 3 years are presented. Annual screening of a cohort of current and former employees is feasible. Original personnel records are often incomplete, making cohort identification important. Personal contact and follow-up are key elements of successful recruitment and retention.