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BACKGROUND: African Americans have higher incidence and mortality from lung cancer than non-Hispanic Whites, but investigations into differences in immune response have been minimal. Therefore, we compared components of the tumor microenvironment among African Americans and non-Hispanic Whites diagnosed with non-small cell lung cancer (NSCLC) based on PD-L1 or tertiary lymphoid structure (TLS) status to identify differences of translational relevance. METHODS: Using a cohort of 280 NSCLC patients from the INHALE study (non-Hispanic White: n=155; African American: n=125), we evaluated PD-L1 tumor proportion score (<1% vs. ≥1%) and TLS status (presence/absence), comparing differences within the tumor microenvironment based on immune cell distribution and differential expression of genes. RESULTS: Tumors from African Americans had a higher proportion of plasma cell signatures within the tumor microenvironment than non-Hispanic Whites. In addition, gene expression patterns in African American PD-L1 positive samples suggest these tumors contained greater numbers of γδ T-cells and resting dendritic cells, along with fewer CD8+ T-cells after adjusting for age, sex, pack-years, stage, and histology. Investigation of differential expression of B-cell/plasma cell related genes between the two patient populations revealed that two immunoglobulin genes (IGKV2-29 and IGLL5) were associated with decreased mortality risk in African Americans. CONCLUSIONS: In the first known race-stratified analysis of tumor microenvironment components in lung cancer based on PD-L1 expression or TLS status, differences within the immune cell composition and transcriptomic signature were identified that may have therapeutic implications. IMPACT: Future investigation of racial variation within the tumor microenvironment may help direct the use of immunotherapy.
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Advances in cancer screening and treatment have improved survival after a diagnosis of cancer. As the number of cancer survivors as well as their overall life-expectancy increases, investigations of health-related quality of life (HRQOL) are critical in understanding the factors that promote the optimal experience over the course of survivorship. However, there is a dearth of information on determinants of HRQOL for African American cancer survivors as the vast majority of cohorts have been conducted predominantly among non-Hispanic Whites. In this review, we provide a review of the literature related to HRQOL in cancer survivors including those in African Americans. We then present a summary of published work from the Detroit Research on Cancer Survivors (ROCS) cohort, a population-based cohort of more than 5000 African American cancer survivors. Overall, Detroit ROCS has markedly advanced our understanding of the unique factors contributing to poorer HRQOL among African Americans with cancer. This work and future studies will help inform potential interventions to improve the long-term health of this patient population.
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BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42â087 patients with NSCLC in the COS-ILCCO database, 21â893 (52·0%) of whom were male and 20â194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37â613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10â841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Femenino , Masculino , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Neoplasias Pulmonares/diagnóstico , Estudios de Cohortes , Fumar/epidemiologíaRESUMEN
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.
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Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Predisposición Genética a la Enfermedad , Detección Precoz del Cáncer , Blanco , Estudio de Asociación del Genoma Completo , Factores de RiesgoRESUMEN
BACKGROUND: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74-0.77) in the training and 0.77 (95% CI, 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. CONCLUSIONS: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Mutación , Análisis de SupervivenciaRESUMEN
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.
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COVID-19 , Supervivientes de Cáncer , Neoplasias , Negro o Afroamericano , Humanos , Neoplasias/epidemiología , Pandemias , SARS-CoV-2RESUMEN
INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, femalesâ¯=â¯47 %; never-smokersâ¯=â¯14 %; White-patientsâ¯=â¯76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHRâ¯=â¯1.66) but not among black patients (aHRâ¯=â¯1.06; pinteractionâ¯=â¯0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteractionâ¯=â¯0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteractionâ¯=â¯0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Índice de Masa Corporal , Femenino , Humanos , Masculino , Sobrepeso/complicaciones , Sobrepeso/epidemiología , Factores de Riesgo , FumarRESUMEN
BACKGROUND: Family history (FH) remains one of the strongest risk factors for many common cancers and is used to determine cancer genetic counseling (CGC) eligibility, but the understanding of familial cancer patterns in African Americans is limited. METHODS: This study evaluated cancer FH among African Americans with invasive breast cancer, prostate cancer, lung cancer, or colorectal cancer (CRC) in the Detroit Research on Cancer Survivors (ROCS) cohort. Associations between participant cancer type, site-specific FH, and meeting national guidelines for CGC were evaluated via logistic regression. Cancer FH patterns were evaluating via hierarchical clustering. RESULTS: Among 1500 ROCS participants, 71% reported at least 1 first-degree relative or grandparent with cancer. FHs of breast cancer, CRC, lung cancer, and prostate cancer were most common among participants with the same diagnosis (odds ratio [OR] for breast cancer, 1.14; P < .001; OR for CRC, 1.08; P = .003; OR for lung cancer, 1.09; P = .008; OR for prostate cancer, 1.14; P < .001). Nearly half of the participants (47%) met national CGC guidelines, and 24.4% of these participants met CGC criteria on the basis of their cancer FH alone. FH was particularly important in determining CGC eligibility for participants with prostate cancer versus breast cancer (OR for FH vs personal history alone, 2.91; 95% confidence interval, 1.94-4.35; P < .001). In clustering analyses, breast and prostate cancer FH-defined clusters were common across all participants. Clustering of CRC and breast cancer FHs was also observed. CONCLUSIONS: ROCS participants reported high rates of cancer FH. The high rate of eligibility for CGC among ROCS participants supports the need for interventions to increase referrals and uptake of CGC among African Americans.
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Asesoramiento Genético/métodos , Neoplasias/genética , Supervivientes de Cáncer , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Anamnesis , Factores de Riesgo , Estados UnidosRESUMEN
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.
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Redes Reguladoras de Genes , Inmunidad , Neoplasias Pulmonares/epidemiología , Polimorfismo de Nucleótido Simple , Enfermedad Pulmonar Obstructiva Crónica/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Especificidad de Órganos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Adulto JovenRESUMEN
INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.
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Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Neoplasias Pulmonares/fisiopatología , Carcinoma Pulmonar de Células Pequeñas/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Factores de Riesgo , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Análisis de Supervivencia , Adulto JovenRESUMEN
PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.
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Procesamiento de Imagen Asistido por Computador/métodos , Procesamiento de Imagen Asistido por Computador/provisión & distribución , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Aprendizaje Automático , Tomografía Computarizada por Rayos X , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estándares de ReferenciaRESUMEN
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.
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Negro o Afroamericano/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes Relacionados con las Neoplasias , Neoplasias Pulmonares/genética , Mutación , Carcinoma de Pulmón de Células no Pequeñas/patología , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Pronóstico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Lung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs. METHODS: We adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays. RESULTS: We identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99-4.22], interferon γ [OR: 1.55; 95% CI: 1.10-2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10-9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92-3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20-2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96-4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09-2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38-0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12-2.21], and tumor necrosis factor ß [OR: 0.52; 95% CI: 0.37-0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences. CONCLUSIONS: Our results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.
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Biomarcadores/sangre , Negro o Afroamericano/estadística & datos numéricos , Mediadores de Inflamación/sangre , Inflamación/complicaciones , Neoplasias Pulmonares/sangre , Población Blanca/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Adulto JovenRESUMEN
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.
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Diagnóstico por Imagen/métodos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico por imagen , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico por imagen , Fumar/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Factores de RiesgoRESUMEN
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.
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Interleucinas/genética , Transducción de Señal/genética , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Pronóstico , Adulto JovenRESUMEN
To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.
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Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 9/genética , Humanos , Pulmón/patología , Anamnesis , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
INTRODUCTION: Lung cancer is a leading cause of cancer-related death worldwide. Racial disparities in lung cancer survival exist between blacks and whites, yet they are limited by categorical definitions of race. We sought to examine the impact of African ancestry on overall survival among blacks and whites with NSCLC cases. METHODS: Incident cases of NSCLC in blacks and whites from the prospective Southern Community Cohort Study (N = 425) were identified through linkage with state cancer registries in 12 southern states. Vital status was determined by linkage with the National Death Index and Social Security Administration. We evaluated the impact of African ancestry (as estimated by using genome-wide ancestry-informative markers) on overall survival by calculating the time-dependent area under the curve (AUC) for Cox proportional hazards models, adjusting for relevant covariates such as stage and treatment. We replicated our findings in an independent population of NSCLC cases in blacks. RESULTS: Global African ancestry was not significantly associated with overall survival among NSCLC cases. There was no change in model performance when Cox proportional hazards models with and without African ancestry were compared (AUC = 0.79 for each model). Removal of stage and treatment reduced the average time-dependent AUC from 0.79 to 0.65. Similar findings were observed in our replication study. CONCLUSIONS: Stage and treatment are more important predictors of survival than African ancestry is. These findings suggest that racial disparities in lung cancer survival may disappear with similar early detection efforts for blacks and whites.
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Disparidades en Atención de Salud/normas , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Grupos Raciales , Análisis de SupervivenciaRESUMEN
Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non-small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54-0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71-0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33-0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene-environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288-95. ©2017 AACR.
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Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Adulto , Negro o Afroamericano , Anciano , Estudios de Cohortes , Femenino , Variación Genética , Humanos , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.
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Consumo de Bebidas Alcohólicas/efectos adversos , Neoplasias Pulmonares/epidemiología , Fumar/efectos adversos , Anciano , Bebidas Alcohólicas/efectos adversos , Asia/epidemiología , Estudios de Casos y Controles , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , América del Norte/epidemiología , Factores de RiesgoRESUMEN
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.