Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here ...we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.
The lower airway bacterial microbiome influences carcinogenesis and response to immunotherapy in non–small cell lung cancer (NSCLC). We investigated the association of this microbiome with recurrence ...in early NSCLC.
Microbiomes of presurgery bronchoalveolar lavage (BAL) and saliva, and resected stage I NSCLC tumor and adjacent lung tissues of 48 patients were examined by 16S gene sequencing. Tumor gene expression was measured by RNA sequencing.
Spatial relationships of the different biospecimen types was reflected in their microbiomes, with microbiomes of BAL intermediate to those of saliva and lung tissue. BAL and saliva microbiomes were less dissimilar in patients with high α-amylase levels in BAL, indicating oral aspiration as a source of lower airway microbiota. BAL microbiomes of patients with recurrence within 32 months of surgery differed from those without recurrence during ≥32 months of follow-up (n = 18 each), despite no difference for age, sex, smoking history, and tumor histology and grade. The recurrence-associated BAL microbiome signature was present in 16 of the 18 recurrence cases but in only two of the others. Signature presence was associated with shorter recurrence-free survival (log-rank test P < .001; hazard ratio = 14.5), and greater expression in tumors of genes for cell proliferation and epithelial mesenchymal transition. Immune cellular composition of the tumor microenvironment was not different between patients with and without the signature.
Presurgery composition of lower airway microbiome may be associated with recurrence of early NSCLC. This association may reflect an influence of the microbiome on tumor biology.
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Lung cancer is the leading cause of cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify ...smokers with premalignant lesions (PMLs) that will progress to invasive cancer. Prior work identified molecular alterations in the smoke-exposed airway field of injury associated with lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in lung cancer chemoprevention.
Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by mRNA-Seq from subjects with (
= 50) and without (
= 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and lung cancer-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a chemoprevention-relevant biomarker.
We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and squamous cell carcinomas (SCC) was also confirmed using published lung cancer datasets. The biomarker performed well predicting the presence of PMLs (AUC = 0.92,
= 17), and changes in the biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75,
= 51).
Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in chemoprevention trials.
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Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has ...provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a "Pre-Cancer Genome Atlas (PCGA)," a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding "field of injury" collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative "big-data" effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention.
Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J ...mice (n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25-hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% (P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity.
Objective/Background: Insomnia occurs in 50 to 80% of lung cancer survivors. Cognitive behavioral therapy is the standard treatment for insomnia (CBTI); however, treatment length and lack of ...psychologists trained in CBTI limits access. Brief Behavioral Treatment for Insomnia (BBTI), a nurse-delivered modified CBTI, is proposed. This feasibility pilot study sought to compare the BBTI intervention to attention control Healthy Eating Program (HEP) for insomnia in lung cancer survivors.
Participants: The participants comprised adults, 21 years of age or older with insomnia and stage I/II non-small cell lung cancer, more than 6 weeks from surgery and living in Western NY.
Methods: Participants (n = 40) were randomly assigned to an experimental (BBTI) or attention control condition (Healthy Eating Program). Thirty participants completed the study.
Results: Participants were 66 years of age (± 7.6; range 53-82), 40% (n = 16) male, 87.5% (n = 35) Caucasian, 50% (n = 20) married, BMI 27.7 (± 5.8), and 12% (n = 5) never smokers. Baseline sleep diary sleep efficiency, ISI and other baseline covariates were balanced between the groups. Sleep efficiency improved ≥85% in BBTI group (p = .02), but not in HEP control group (p = 1.00). Mean ISI for BBTI and attention control were 6.40 ± 4.98 and 14.10 ± 4.48 (p = .001) respectively. In addition, BBTI group mean total FACT-L score improved by 6.66 points from baseline while HEP group score worsened (p = .049).
Conclusions: BBTI is a practical, evidence-based, clinically relevant intervention that improved sleep and quality of life in lung cancer survivors with insomnia. Additional research to evaluate efficacy, duration, and implementation strategies are essential.
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