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There is increased incidence of prostate cancer (PC) among World Trade Center (WTC)-exposed responders and community members, with preliminary evidence suggestive of more aggressive disease. While previous research is supportive of differences in DNA methylation and gene expression as a consequence of WTC exposure, as measured in blood of healthy individuals, the epigenetics of WTC PC tissues has yet to be explored. Patients were recruited from the World Trade Center Health Program. Non-WTC PC samples were frequency matched on age, race/ethnicity and Gleason score. Bisulfite-treated DNA was extracted from tumor tissue blocks and used to assess global DNA methylation with the MethylationEPIC BeadChip. Differential and pathway enrichment analyses were conducted. RNA from the same tumor blocks was used for gene expression analysis to further support DNA methylation findings. Methylation data were generated for 28 samples (13 WTC and 15 non-WTC). Statistically significant differences in methylation were observed for 3,586 genes; on average WTC samples were statistically significantly more hypermethylated (P = 0.04131). Pathway enrichment analysis revealed hypermethylation in epithelial mesenchymal transition (EMT), hypoxia, mitotic spindle, TNFA signaling via NFKB, WNT signaling, and TGF beta signaling pathways in WTC compared to non-WTC samples. The androgen response, G2M and MYC target pathways were hypomethylated. These results correlated well with RNA gene expression. In conclusion, long-term epigenic changes associated with WTC dust exposure were observed in PC tissues. These occurred in genes of critical pathways, likely increasing prostate tumorigenesis potential. This warrants analysis of larger WTC groups and other cancer types.

ObjectiveTo explore the regulation of the inflammatory response in acute SARS-CoV-2 infection, we examined effects of single nucleotide variants (SNVs) ofIL1RN, the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality.MethodsWe studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021 at NYU Langone’s Tisch Hospital. CTA and TTG haplotypes formed from three SNVs (rs419598, rs315952, rs9005) and the individual SNVs of theIL1RNgene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality.ResultsMortality in the population was 15.3%, and was lower in women than men (13.1% vs.17.3%, pIL1RNhaplotypes exhibiteddecreasedinflammatory markers andincreasedplasma IL-1Ra relative to TTG carriers. Decreased mortality among CTA-1/2 carriers was observed in male patients between the ages of 55-74 [9.2% vs. 17.9%, p=0.001]. Evaluation of individual SNVs of theIL1RNgene (rs419598, rs315952, rs9005) indicated that carriers of theIL1RNrs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 – 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, pConclusionTheIL1RNhaplotype CTA, and sequence variant of rs419598 are associated with attenuation of the cytokine release syndrome and decreased mortality in males with acute SARS-CoV2 infection. The data suggest thatIL1RNmodulates the COVID-19 cytokine release syndrome via endogenous “ anti-inflammatory” mechanisms.Significance statementWe provide evidence that variants ofIL1RNmodulate the severity of SARS-CoV-2 infection. TheIL1RN CTA haplotype andrs419598 CC single nucleotide variant are associated with decreased plasma levels of inflammatory markers, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin, in association with higher levels of IL-1Ra and IL-10, anti-inflammatory proteins. Both haplotype CTA and rs419598 CC genotype are associated with a significant reduction in the mortality of men. These data provide genetic evidence that inflammasome activation and the IL-1 pathway plays an important role in the mortality and morbidity associated with severe SARS-CoV-2 infection, and that genetic regulation of inflammatory pathways by variants ofIL1RNmerits further evaluation in severe SARS-CoV-2 infection.

Introduction The role of specific immune cell types within the tumor immune microenvironment in non-small cell lung cancer survival is unclear. The potential of these immune cells to become predictive biomarkers of prognosis, and to define subpopulations who will benefit of additional treatment is urgently needed. Methods Stage I to IIIA non-small cell lung cancer patients who underwent surgical resection were queried from the Cancer Genome Atlas; RNAseq data as well as clinical information was extracted. Sample-specific scores for different immune cells were computed via xCell. The association between each cell type and survival was assessed with Cox regression, both unadjusted and adjusted for sex, stage, smoking status, and tumor purity. Models were stratified by lung adenocarcinoma and lung squamous cell carcinoma. Results There were 383 lung adenocarcinoma and 328 lung squamous cell carcinoma samples, and 161 (42%) and 124 (38%) deaths respectively. There was no association between any immune cell infiltrations and survival in the combined unadjusted Cox regression model. After adjustment, the presence of CD8+ cytotoxic T cells (adjusted hazard ratio [HRajd]: 0.84; 95% confidence interval [CI]: 0.71-0.99; P=0.03), CD4+ helper T cells (HRajd: 0.79; 95% CI: 0.66-0.95; P=0.01) and CD20+ B cells (HRajd: 0.80; 95% CI: 0.66-0.97; P=0.02) were significant predictors of decreased risk of death. Conclusions This study shows that the adjustment for clinical characteristics is key when evaluating tumor immune infiltration and its association with cancer outcomes. Adjustment for confounding factors modified the prognostic significance of specific immune cell populations in early-stage surgically resected NSCLC cases; clinical attributes may have high relevance on immune infiltration composition.

A research initiative was launched during the initial coronavirus disease (COVID-19) outbreak by 3 New York metropolitan area institutions. Collaborators recruited community members and patients from previous research studies to examine COVID-19 experiences and mental health symptoms through self-report surveys. The current report descriptively presents findings from the initial survey characterized by both community and clinical cohorts, and discusses challenges encountered with rapid implementation. The clinical cohort exhibited higher rates of symptoms of mental health difficulties (depression, anxiety, and posttraumatic stress disorder [PTSD]) as compared to the community cohort. COVID-19 positivity rates were similar among both groups and lower than the national average. While both groups reported low rates of job loss, community members reported higher rates of financial difficulty resulting from the pandemic. Findings indicate the need for further collaborative research on the mental health impact of COVID-19.

OBJECTIVES Sociodemographic disparities in lung cancer prevalence, treatment options offered, and outcomes have been well documented. In stage I non-small cell lung cancer (NSCLC), the standard of care is surgical resection. This study explores disparities in surgical recommendations in stage I NSCLC, when surgery is considered curative. MATERIALS AND METHODS Patients diagnosed with primary stage I NSCLC from 2007 to 2016 were identified from the Surveillance, Epidemiology, and End Results database (N=56,534). Associations between sociodemographic variables and surgical recommendation were assessed using multivariable logistic regression models. Survival impact was investigated using Cox-proportional hazards regression and propensity matching techniques. RESULTS Of the 76.9% patients recommended surgery, 95% underwent surgery. Recommended surgery was inversely associated with increasing age (P

Background Although immunotherapy can increase survival in non-small cell lung cancer (NSCLC), response rates are low. It is unclear which characteristics contribute to variability in immunotherapy efficacy and survival. Research is needed to identify reasons for heterogeneity in response rates to better tailor treatments. Methods Web of Science, Ovid EMBASE, and MEDLINE were queried from 2013 to January 2021, and all studies reporting overall or progression-free survival for patients treated with immunotherapy for NSCLC of at least stage IIIB were screened. Results Included were 18 randomized controlled trials (RCTs; 6534 immunotherapy RCTs; 11 192 nonimmunotherapy RCTs) and 16 observational studies (n = 9073 immunotherapy patients). Among RCTs, there was improved survival with the addition of immunotherapy in patients aged younger than 65 years in 10 of 17 studies; smokers in 8 of 15 studies; and males in 10 of 17 studies and 6 of 17 females. Only 5 studies reported outcomes by race. Among observational studies, younger patients (aged younger than 60, younger than 65, or younger than 70 years in most studies) had better survival than older patients (aged 60 years and older, 65 years and older, or 70 years and older) in 4 of 13 studies, ever-smokers in 7 of 13, and females in 2 of 14. Three studies reported race with mixed results. Conclusion Although evidence is mixed, younger patients, smokers, and males may derive more benefit from immunotherapy. Evidence on racial differences is limited. Physicians should be mindful of personal characteristics when formulating treatment plans. Further research is needed to understand underlying mechanisms and to identify the best immunotherapy candidates and alternative treatments for those unlikely to benefit.

Breast cancer represents the most common cancer diagnosis among World Trade Center (WTC)-exposed community members, residents, and cleanup workers enrolled in the WTC Environmental Health Center (WTC EHC). The primary aims of this study were (1) to compare blood DNA methylation profiles of WTC-exposed community members with breast cancer and WTC-unexposed pre-diagnostic breast cancer blood samples, and (2) to compare the DNA methylation differences among the WTC EHC breast cancer cases and WTC-exposed cancer-free controls. Gene pathway enrichment analyses were further conducted. There were significant differences in DNA methylation between WTC-exposed breast cancer cases and unexposed prediagnostic breast cancer cases. The top differentially methylated genes were Intraflagellar Transport 74 (IFT74), WD repeat-containing protein 90 (WDR90), and Oncomodulin (OCM), which are commonly upregulated in tumors. Probes associated with established tumor suppressor genes (ATM, BRCA1, PALB2, and TP53) were hypermethylated among WTC-exposed breast cancer cases compared to the unexposed group. When comparing WTC EHC breast cancer cases vs. cancer-free controls, there appeared to be global hypomethylation among WTC-exposed breast cancer cases compared to exposed controls. Functional pathway analysis revealed enrichment of several gene pathways in WTC-exposed breast cancer cases including endocytosis, proteoglycans in cancer, regulation of actin cytoskeleton, axon guidance, focal adhesion, calcium signaling, cGMP-PKG signaling, mTOR, Hippo, and oxytocin signaling. The results suggest potential epigenetic links between WTC exposure and breast cancer in local community members enrolled in the WTC EHC program.

// Stephanie Tuminello 1 , Rajwanth Veluswamy 1 , 2 , Wil Lieberman-Cribbin 1 , Sacha Gnjatic 2 , 3 , 4 , Francesca Petralia 5 , Pei Wang 5 , Raja Flores 6 and Emanuela Taioli 1 , 6 , 7 1 Institute for Translational Epidemiology and Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA 2 Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 3 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA 4 Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA 5 Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA 6 Department of Thoracic Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA 7 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Correspondence to: Emanuela Taioli, email: Emanuela.taioli@mountsinai.org Keywords: NSCLC; immune contexture; tumor microenvironment; TILs Received: September 18, 2019 Accepted: December 05, 2019 Published: December 24, 2019 ABSTRACT Background: Early-stage non-small cell lung cancer (NSCLC) patients carry significant risk of recurrence post-surgery. In-depth characterization of the immune tumor microenvironment (TME) can have prognostic value. This study aimed to evaluate the association of individual immune cell types in the TME with clinical outcomes in surgically resected, early-stage NSCLC. Methods: We performed a systematic literature search of the National Library of Medicine database through November 2019, investigating predefined biomarkers (CD3+ T cells, CD4+ T helper cells, CD8+ cytotoxic T cells, CD20+ B cells, CD56+ & CD57+ Natural Killer (NK) cells, CD68+ Tissue Associated Macrophages (TAMS), FoxP3+ T regulatory cells, and Mast Cells (MC)), and their association with survival following PRISMA guidelines. Results: Studies that adjusted for important clinical covariates (such as stage and age) showed that higher levels of CD8+ cytotoxic T cells were associated with improved OS (HR = 0.68; 95% CI, 0.50–0.93) and DFS (HR = 0.60; 95% CI, 0.41–0.87), while increased CD20+ B cells (HR = 0.16; 95% CI, 0.04–0.64) and CD 56/57+ NK cells (HR = 0.50; 95% CI, 0.26–0.95) were associated with improved OS; lung cancers with increased FoxP3+ T regulatory cells (HR = 2.22; 95% CI, 1.47–3.34) had worse OS. Conclusions: Immune cell components of the TME have prognostic value in early-stage, surgically resected NSCLC, and may reveal which patients are more likely to need additional systemic treatment, including immunotherapy. Clinical covariates need to be considered when evaluating the prognostic value of immune cells in the TME.

For early-stage cancer surgery is often curative, yet refusal of recommended surgical interventions may be contributing to disparities in patient treatment. This study aims to assess predictors of early-stage cancers surgery refusal, and the impact on survival. Patients recommended surgery with primary stage I and II lung, prostate, breast, and colon cancers, diagnosed between 2007–2014, were identified in the Surveillance, Epidemiology and End Results database (n = 498,927). Surgery refusal was reported for 5,757 (1.2%) patients. Associations between sociodemographic variables and surgery refusal by cancer type were assessed in adjusted multivariable logistic regression models. The impact of refusal on survival was investigated using adjusted Cox-Proportional Hazard regression in a propensity score-matched cohort. Increasing age (p

BACKGROUND: PD-L1 tumor expression has been associated with poor prognosis in a variety of solid tumors, including lung cancer, and represents a validated target for immune checkpoint inhibition in advanced malignances. It remains unknown, however, if PD-L1 can be used to predict survival in early stage, surgically treated cancers. This meta-analysis compares PD-L1 tumor expression and long term survival after surgical resection in early non-small cell lung cancer (NSCLC). METHODS: PubMed was searched to identify eligible studies that compared survival of surgically resected stage I–III NSCLC patients according to PD-L1 tumor expression. Included studies were grouped according to measurement criteria of PD-L1 expression: 1%, 5%, 50% cutoffs or H-score. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS). I(2) was used as a measure of heterogeneity. RESULTS: There were 40 eligible studies, including 10,380 patients. Regardless of cut-off used, higher PD-L1 tumor expression was associated with worse OS [hazard ratio (HR)(1%): 1.59, 95% confidence interval (CI), 1.17–2.17; HR(5%): 1.44, 95% CI, 1.03–2.00; HR(50%): 1.52, 95% CI, 1.02–2.25, HR(H-score): 1.34, 95% CI, 1.04–1.73]. Study heterogeneity was low and not statistically significant under all PD-L1 cutoffs. CONCLUSIONS: PD-L1 expression is consistently associated with worse survival, regardless of how it is quantified. In addition to acting as a prognostic biomarker, PD-L1 may also be used in future as a predictive biomarker for patients most likely to benefit from adjuvant immunotherapy.

The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.

Introduction Existing socioeconomic and racial disparities in healthcare access in New York City have likely impacted the public health response to coronavirus disease 2019 (COVID-19). An ecological study was performed to determine the spatial distribution of COVID-19 testing by ZIP Code Tabulation Area and investigate if testing was associated with race or SES. Methods Data were obtained from the New York City Coronavirus data repository and the 2018 American Community Survey 5-year estimates. A combined index of SES was created using principal component analysis, and incorporated household income, gross rent, poverty, education, working class status, unemployment, and occupants per room. Multivariable Poisson regressions were performed to predict the number of total tests and the ratio of positive tests to total tests performed, using the SES index, racial composition, and Hispanic composition as predictors. Results The number of total tests significantly increased with the increasing proportion of white residents (β=0.004, SE=0.001, p=0.0032), but not with increasing Hispanic composition or SES index score. The ratio of positive tests to total tests significantly decreased with the increasing proportion of white residents in the ZIP Code Tabulation Area (β= –0.003, SE=0.0006, p

Hurricane exposure can have a profound impact on mental health, leading to increased symptoms of stress, anxiety, depression and post-traumatic stress disorder that are still present years after the storm. Those displaced following a hurricane are particularly vulnerable to adverse mental health outcomes, especially if displaced to temporary shelters. The current work highlights the experiences and mental health challenges of displaced populations following Hurricane Sandy and Hurricane Harvey, as well as describing barriers to conducting research in the immediate aftermath of Hurricane Harvey and the need for more comprehensive interventions in these vulnerable populations.

World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. New York University (NYU) and Mount Sinai have recreated WTC exposure in rodents to observe the resulting systemic and local biological responses. These experiments aid in the interpretation of epidemiological observations and are useful for understanding the carcinogenesis process in the exposed human WTC cohort. Here we describe the implementation of a tissue bank system for the rodents experimentally exposed to WTC dust. NYU samples were experimentally exposed to WTC dust via intratracheal inhalation that mimicked conditions in the immediate aftermath of the disaster. Tissue from Mount Sinai was derived from genetically modified mice exposed to WTC dust via nasal instillation. All processed tissues include annotations of the experimental design, WTC dust concentration/dose, exposure route and duration, genetic background of the rodent, and method of tissue isolation/storage. A biobank of tissue from rodents exposed to WTC dust has been compiled representing an important resource for the scientific community. The biobank remains available as a scientific resource for future research through established mechanisms for samples request and utilization. Studies using the WTC tissue bank would benefit from confirming their findings in corresponding tissues from organs of animals experimentally exposed to WTC dust. Studies on rodent tissues will advance the understanding of the biology of the tumors developed by WTC responders and ultimately impact the modalities of treatment, and the probability of success and survival of WTC cancer patients.

Thyroid cancer incidence is higher in World Trade Center (WTC) responders compared with the general population. It is unclear whether this excess in thyroid cancer is associated with WTC-related exposures or if instead there is an over-diagnosis of malignant thyroid cancer among WTC first responders due to enhanced surveillance and physician bias. To maximize diagnostic yield and determine the false positive rate for malignancy, the histological diagnoses of thyroid cancer tumors from WTC responders and age, gender, and histology matched non-WTC thyroid cancer cases were evaluated using biomarkers of malignancy. Using a highly accurate panel of four biomarkers that are able to distinguish benign from malignant thyroid cancer, our results suggest that over-diagnosis by virtue of misdiagnosis of a benign tumor as malignant does not explain the increased incidence of thyroid cancer observed in WTC responders. Therefore, rather than over-diagnosis due to physician bias, the yearly screening visits by the World Trade Center Health Program are identifying true cases of thyroid cancer. Continuing regular screening of this cohort is thus warranted.

An increased incidence of thyroid cancer among 9/11 rescue workers has been reported, the etiology of which remains unclear but which may, at least partly, be the result of the increased medical surveillance this group undergoes. This study aimed to investigate thyroid cancer in World Trade Center (WTC) responders by looking at the demographic data and questionnaire responses of thyroid cancer cases from the Mount Sinai WTC Health Program (WTCHP). WTCHP thyroid cancer tumors were of a similar size (p = 0.4), and were diagnosed at a similar age (p = 0.2) compared to a subset of thyroid cancer cases treated at Mount Sinai without WTC exposure. These results do not support the surveillance bias hypothesis, under which smaller tumors are expected to be diagnosed at earlier ages. WTCHP thyroid cancer cases also reported a past history of radiation exposure and a family history of thyroid conditions at lower rates than expected, with higher than expected rates of previous cancer diagnoses, family histories of other cancers, and high Body Mass Indexes (BMIs). Further research is needed to better understand the underlying risk factors that may play a role in the development of thyroid cancer in this group.

Background World Trade Center (WTC) responders were exposed to mixture of dust, smoke, chemicals and carcinogens. Studies of cancer incidence in this population have reported elevated risks of cancer compared to the general population. There is a need to supplement current epidemiologic cancer follow-up with a cancer tissue bank in order to better elucidate a possible connection between each cancer and past WTC exposure. This work describes the implementation of a tissue bank system for the WTC newly diagnosed cancers, focused on advancing the understanding of the biology of these tumors. This will ultimately impact the modalities of treatment, and the probability of success and survival of these patients. Methods WTC Responders who participated (as employees or volunteers) in the rescue, recovery and cleanup efforts at the WTC sites have been enrolled at Mount Sinai in the World Trade Center Health Program. Responders with cancer identified and validated through linkages with New York, New Jersey, Pennsylvania, and Connecticut cancer registries were eligible to participate in this biobank. Potential participants were contacted through letters, phone calls, and emails to explain the research study, consent process, and to obtain the location where their cancer procedure was performed. Pathology departments were contacted to identify and request tissue samples. Results All the 866 solid cancer cases confirmed by the Data Center at Mount Sinai have been contacted and consent was requested for retrieval and storage of the tissue samples from their cancer. Hospitals and doctors’ offices were then contacted to locate and identify the correct tissue block for each patient. The majority of these cases consist of archival paraffin blocks from surgical patients treated from 2002 to 2015. At the time of manuscript writing, this resulted in 280 cancer samples stored in the biobank. Conclusions A biobank of cancer tissue from WTC responders has been compiled with 280 specimens in storage to date. This tissue bank represents an important resource for the scientific community allowing for high impact studies on environmental exposures and cancer etiology, cancer outcome, and gene-environment interaction in the unique population of WTC responders.

Objective Sublobar resection is often used as an alternative surgical approach in lung cancer patients who are unlikely to tolerate a full lobe resection. This study aims to assess outcomes of video-assisted thoracoscopic surgeries (VATS) sublobar resection as a surgical technique. Materials and methods The SEER-Medicare database was queried to identify patients with primary lung cancer who had VATS or open sublobar resection. Baseline clinical differences between VATS and open patients were adjusted for in logistic regression and by propensity score matching to investigate surgical outcomes. Results Patients undergoing VATS had a greater number of comorbidities (adjusted odds ratio [ORadj], 0.90; 95% confidence interval [CI], 0.85-0.96) and were less likely to have later stage cancer (ORadj, 0.80; 95% CI, 0.67-0.95), squamous compared with adenocarcinoma (ORadj, 0.82; 95% CI, 0.68-0.99), large (>30 mm) tumor size (ORadj, 0.56; 95% CI, 0.0.41-0.75). VATS patients were less likely to have nodes removed for examination during surgery (ORadj, 0.76; 95% CI, 0.64-0.90). After propensity matching (n=2148), patients who underwent VATS were less likely to experience in-hospital complications, blood transfusions, and a prolonged length of hospital stay than those who had open surgery. There was no statistically significant difference in in-hospital or long-term mortality between patients with VATS and open surgery. Conclusion In the most compromised lung cancer patients, VATS sublobar resection might be the best option.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours., The mechanisms that govern the transdifferentiation of lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) are not fully understood. Here, the authors show that EZH2 loss exacerbates the transdifferentiation of ADCs to SCCs as a result of chromatin changes that lead to expression of squamous differentiation genes.

Adenosquamous lung tumours, which are extremely poor prognosis, may result from cellular plasticity. Here, we demonstrate lineage switching of KRAS+ lung adenocarcinomas (ADC) to squamous cell carcinoma (SCC) through deletion of Lkb1 (Stk11) in autochthonous and transplant models. Chromatin analysis reveals loss of H3K27me3 and gain of H3K27ac and H3K4me3 at squamous lineage genes, including Sox2, ΔNp63 and Ngfr. SCC lesions have higher levels of the H3K27 methyltransferase EZH2 than the ADC lesions, but there is a clear lack of the essential Polycomb Repressive Complex 2 (PRC2) subunit EED in the SCC lesions. The pattern of high EZH2, but low H3K27me3 mark, is also prevalent in human lung SCC and SCC regions within ADSCC tumours. Using FACS-isolated populations, we demonstrate that bronchioalveolar stem cells and club cells are the likely cells-of-origin for SCC transitioned tumours. These findings shed light on the epigenetics and cellular origins of lineage-specific lung tumours.

OBJECTIVES/SPECIFIC AIMS: Immune cells within the tumor microenvironment (TME) play an important role in the development and progression of non-small cell lung cancer (NSCLC). However, data evaluating the impact of individual immune cell types on NSCLC outcomes is limited and often conflicting. We performed a meta-analysis of existing data and used The Cancer Genome Atlas (TCGA) to evaluate the effect of several immune cells on surgical outcomes of stage I-IIIA NSCLC. METHODS/STUDY POPULATION: PubMed was searched to identify eligible studies evaluating survival of surgically resected stage I-IIIA NSCLC patients according to immune cell infiltration. Meta-analysis was performed using a linear mixed-effects model to determine overall, disease specific and progression free survival. We then used a similar patient subset found in the TCGA to validate the meta-analysis findings. For the TCGA analysis, sample-specific scores for different immune cells were computed via xCell using level three RNAseq data. After stratifying the cohort by histologic subtype, the association between each cell type and survival was assessed via Cox Regression, while adjusting for stage, gender and smoking status. RESULTS/ANTICIPATED RESULTS: From the meta-analysis (37 articles eligible; N = 8,162 patients), high levels of CD20+ B cells (hazard ratio [HR]: 0.36, 95% confidence interval [CI]: 0.15-0.85), natural killer (NK) cells (HR: 0.64, 95% CI: 0.41-1.0), and dendritic cells (0.34, 95% CI: 0.13-0.84) were significantly associated with better overall survival (OS); T regulatory cells (HR: 1.85, 95% CI: 1.35-2.54) were associated with worst OS. High CD8+ T cell infiltrates were associated with improved disease-free survival (DFS; HR: 0.85, 95% CI 0.73-0.99), while CD68+ macrophages (HR> 2.83, 95% CI: 1.28-6.24) were associated with worst DFS. In the TCGA cohort, lung adenocarcinomas rich in CD4 T cells, CD8 T cells, B cells, and NK cells were associated with improved OS in unadjusted analysis. In adjusted analysis, only NK cells were associated with improved OS (HR: 0.82, 95% CI: 0.69-0.98). There was no significant association of any immune cell type for DFS in lung adenocarcinomas and with both OS and DFS in Squamous Cell Lung Cancers (p>0.05 for all comparisons). DISCUSSION/SIGNIFICANCE OF IMPACT: The presence of tumor infiltration by specific immune cell subsets may potentially predict survival outcomes in resected stage I-III NSCLC patients. However, the impact of immune cells may not be similar in all histologic types and after adjusting for important clinical confounders.

This population-based study compares opioid use in patients with non–small cell lung cancer who underwent open resection vs video-assisted thoracoscopic surgery.

Hurricane Harvey made landfall in Houston, Texas on 25 August 2017, the psychological and physical effects of which are still unknown. We assessed hurricane exposure and the immediate mental health needs of the population to define public health priorities for a larger epidemiological study. Convenience sampling was used to recruit participants (n = 41) from the greater Houston area aged ≥18 years. Participants completed a questionnaire about demographics, hurricane exposures, and physical/mental health. Post-Traumatic Stress Disorder (PTSD) was measured with the Post-Traumatic Stress Disorder Checklist-S (PCL-S; a score ≥30 indicated probable PTSD symptoms). The Patient Health Questionnaire-4 (PHQ-4) was used to assess symptoms of depression and generalized anxiety disorder. The average PTSD score was 32.9 (SD = 17.1); a total of 46% of participants met the threshold for probable PTSD. Increased overall hurricane exposure (adjusted odds ratio (ORadj) 1.42; 95% confidence interval (CI): 1.06–2.05) and property-related exposure (ORadj 1.53; 95% CI: 1.07–2.18) were both statistically significantly associated with increased odds of probable PTSD symptoms. A perception of chemical/toxin exposure due to Hurricane Harvey was reported by 44% of participants. A higher number of personal or property exposures were associated with greater mental health symptoms three weeks post-hurricane. This work has implications for the ongoing response to Hurricane Harvey and for assessing the immediate needs of the population.

We previously discovered that the targeted focus of the most significant amplicon in squamous cell lung cancer lies on the SOX2 gene locus, a product of which is a critical regulator in specifying squamous cell lineages in the development at dividing foregut to counteract with NKX2-1, which specifies tracheal and later lung lineages and is the most significantly amplified gene in lung adenocarcinoma. Cell lines harboring such amplification from respective lung cancer subtypes are dependent on the expression of these lineage-determining factors for their survival. However, the amplifications of these factors represent only 10-15% of lung cancer, it remains unknown what other lineage programs the remaining majority rely upon. Posttranslational modifications of histone proteins assign different functional regions of the genome, which leads to chromatin states that create stable expression patterns maintaining cellular fates. Studies on genome-wide enhancers have revealed the presence of large enhancer clusters, which are typically enriched in the proximity of lineage factor genes that establish a program defining cellular identity. To identify novel subsets of lung cancer defined by chromatin modification on lineage-determining factors, we made use of a histone modification marker H3K27Ac, typically present at active enhancers. We profiled H3K27Ac by ChIP-seq in 24 cell lines (14 lung adenocarcinoma, 4 squamous cell carcinoma, 4 small cell lung cancer and 2 breast carcinoma), identifying thousands of active enhancers, i.e. H3K27Ac enriched, and hundreds of super-enhancers (SEs) defined by ROSE algorithm per cell line. As a proof of principle, we found a locus adjacent to NKX2-1 gene as one of the SEs in an NKX2-1-amplified cell line NCI-H3122, suggesting this approach can detect a lineage program that is overridden by cancer cells. We performed unsupervised hierarchical clustering analyses on signals at SEs adjacent to transcriptional regulatory genes and identified unique subsets segregated primarily by their lineages. Several SEs on transcription factors are common between multiple cell lines from the same lineage (e.g., SOX2 and TP63 in squamous cell lineage and NKX2-1 in lung adenocarcinoma lineage). We identified 6 lung adenocarcinoma cell lines that contain SE at the locus of NR4A2, a significantly mutated gene in lung adenocarcinomas, and 2 other lines at the locus of HOPX, a lineage transcription factor for alveolar type I cells. These results suggest that this approach can reveal novel enhancers on lineage factors in a subset of lung cancers. Note: This abstract was not presented at the meeting. Citation Format: Stephanie Tuminello, Hideo Watanabe, Takashi Sato. Enhancer signature profiling identifies novel enhancer clusters for transcription factors in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2017-3363