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.

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.

Introduction: Known carcinogens in the dust and fumes from the destruction of the World Trade Center (WTC) towers on 9 November 2001 included metals, asbestos, and organic pollutants, which have been shown to modify epigenetic status. Epigenome-wide association analyses (EWAS) using uniform (Illumina) methodology have identified novel epigenetic profiles of WTC exposure. Methods: We reviewed all published data, comparing differentially methylated gene profiles identified in the prior EWAS studies of WTC exposure. This included DNA methylation changes in blood-derived DNA from cases of cancer-free “Survivors” and those with breast cancer, as well as tissue-derived DNA from “Responders” with prostate cancer. Emerging molecular pathways related to the observed DNA methylation changes in WTC-exposed groups were explored and summarized. Results: WTC dust exposure appears to be associated with DNA methylation changes across the genome. Notably, WTC dust exposure appears to be associated with increased global DNA methylation; direct dysregulation of cancer genes and pathways, including inflammation and immune system dysregulation; and endocrine system disruption, as well as disruption of cholesterol homeostasis and lipid metabolism. Conclusion: WTC dust exposure appears to be associated with biologically meaningful DNA methylation changes, with implications for carcinogenesis and development of other chronic diseases.

The collapse of the World Trade Center (WTC) buildings in New York City generated a large plume of dust and smoke. WTC dust contained human carcinogens including metals, asbestos, polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs, including polychlorinated biphenyls (PCBs) and dioxins), and benzene. Excess levels of many of these carcinogens have been detected in biological samples of WTC-exposed persons, for whom cancer risk is elevated. As confirmed in this structured literature review (n studies = 80), all carcinogens present in the settled WTC dust (metals, asbestos, benzene, PAHs, POPs) have previously been shown to be associated with DNA methylation dysregulation of key cancer-related genes and pathways. DNA methylation is, therefore, a likely molecular mechanism through which WTC exposures may influence the process of carcinogenesis.

Personalized medicine, including targeted and immunotherapy, has substantially changed the landscape of non-small cell lung cancer (NSCLC). About 30% of NSCLC tumors have targetable mutations, like EGFR, and 28% of tumors will have a PD-L1 score or tumor mutation burden high enough to warrant immunotherapy; a molecular test prior to therapy assesses eligibility. However, the congruence between testing and treatment, and the effect of treatment without testing on outcomes, is understudied. We extracted a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data. The primary outcome was survival. Demographic and clinical characteristics of those receiving vs. not receiving a molecular test were compared, and a Kaplan–Meier curve along with a multivariable Cox proportional hazards regression assessed the association of survival with the receipt of molecular diagnostic testing, adjusting for sex, race, age, income tract, metro/urban/rural region, histology, and stage. There were 911 NSCLC patients treated with personalized therapy, of which 513 (56.3%) had received prior molecular testing. Black patients were less likely than White patients to receive testing (36.4% vs. 59.9%; p < 0.001). Testing was significantly more frequent in patients with fewer comorbidities (p < 0.001), adenocarcinoma (p = 0.004), tumors in the lower lobe (p = 0.037), or diagnosed at a later stage (p = 0.026). Only 39.9% of patients receiving EGFR inhibitors were initially tested for an EGFR mutation. Among NSCLC patients treated with personalized therapy, untested patients were at increased mortality risk compared to tested patients (median survival 8.22 vs. 12.79 months, p = 0.024). After adjustment, treated patients not tested beforehand had a significantly higher mortality risk (HRadj: 1.20; 95% CI: 1.04–1.40). Substantial incongruence between receipt of molecular testing and personalized therapies exists according to nationwide claims data, with only about half of treated patients having had an appropriate molecular diagnostic workup. This could explain, in part, the higher mortality among treated patients who did not undergo testing. Before expanding personalized therapies, further addressing these issues through standardized, reflexive testing protocols and improved clinician education is critical to optimizing the integration of molecular diagnostics into treatment planning.

Immunotherapy has improved survival in patients with advanced NSCLC. Efficacy may decrease when patients are treated with antibiotics, possibly due to gut microbiome disruption, but few studies have investigated this using real-world, patient-level populations in the United States. We have analyzed antibiotic use in patients with stage IV first, primary NSCLC diagnosed in 2015 and treated with chemotherapy or chemoimmunotherapy, drawn from the Surveillance, Epidemiology, and End Results-Medicare data set. Patients had to have continuous part A, part B, and part D Medicare coverage. Survival was determined through Kaplan-Meier and Cox proportional hazards models. All data analyses were performed using SAS. The study included 788 patients, 440 (56%) of whom received antibiotics within 2 months before or after starting systemic treatment. The median follow-up time was 11.64 months. There was a statistically significant difference in survival for patients who received antibiotics (p = 0.007) and who had more than 1 round of antibiotics versus zero or 1 round (p < 0.0001). After adjustment, receipt of antibiotics (hazard ratio [HR]_adj: 1.17, 95% confidence interval [CI]: 0.99-1.37) and receipt of multiple rounds of antibiotics (HR_adj: 1.35, 95% CI: 1.14-1.60) were statistically significantly associated with worse survival. Among just those receiving chemoimmunotherapy (n = 203; 26%), there was still an increased risk of death for those receiving multiple antibiotic rounds (HR_adj: 1.52, 95% CI: 1.09-2.13). Antibiotic use concurrent with chemoimmunotherapy seems to be associated with worse survival. This is more pronounced when more cycles of antibiotics are given. STUDY-19-00500.