A call from 40 public health scientists for an end to the continuing humanitarian and environmental catastrophe in Gaza.

An under-recognised aspect of the current humanitarian catastrophe in Gaza is the impact of the war on the environment and the associated risks for human health. This commentary contextualises these impacts against the background of human suffering produced by the overwhelming violence associated with the use of military force against the general population of Gaza. In calling for an immediate cessation to the violence, the authors draw attention to the urgent need to rebuild the health care system and restore the physical and human infrastructure that makes a liveable environment possible and promotes human health and well-being, especially for the most vulnerable in the population. Environmental remediation should therefore form one of the most important parts of international efforts to assist reconstruction, through which we hope Palestinians and Israelis will achieve lasting peace, health, and sustainable development, all as part of accepted international human rights obligations.

Antibodies to oral pathobionts and colon cancer risk in the CLUE I cohort study.

Periodontitis has been associated with an increased risk for gastrointestinal cancers. The objective of our study was to investigate the association of antibodies to oral bacteria and the risk of colon cancer in a cohort setting. Using the CLUE I cohort, a prospective cohort initiated in 1974 in Washington County, Maryland, we conducted a nested case-control study to examine the association of levels of IgG antibodies to 11 oral bacterial species (13 total strains) with risk of colon cancer diagnosed a median of 16 years later (range: 1-26 years). Antibody response was measured using checkerboard immunoblotting assays. We included 200 colon cancer cases and 200 controls matched on age, sex, cigarette smoking status, time of blood draw and pipe or cigar smoking status. Controls were selected using incidence density sampling. Conditional logistic regression models were used to assess the association between antibody levels and colon cancer risk. In the overall analysis, we observed significant inverse associations for 6 of the 13 antibodies measured (P-trends <.05) and one positive association for antibody levels to Aggregatibacter actinomycetemcomitans (ATCC 29523; P-trend = .04). While we cannot rule out a role for periodontal disease in colon cancer risk, findings from our study suggest that a strong adaptive immune response may be associated with a lower risk of colon cancer. More studies will need to examine whether the positive associations we observed with antibodies to A. actinomycetemcomitans reflect a true causal association for this bacterium.

Epigenome-wide association study using peripheral blood leukocytes identifies genomic regions associated with periodontal disease and edentulism in the Atherosclerosis Risk in Communities study.

AIM: To investigate individual susceptibility to periodontitis by conducting an epigenome-wide association study using peripheral blood. MATERIALS AND METHODS: We included 1077 African American and 457 European American participants of the Atherosclerosis Risk in Communities (ARIC) study who had completed a dental examination or reported being edentulous at Visit 4 and had available data on DNA methylation from Visit 2 or 3. DNA methylation levels were compared by periodontal disease severity and edentulism through discovery analyses and subsequent testing of individual CpGs. RESULTS: Our discovery analysis replicated findings from a previous study reporting a region in gene ZFP57 (6p22.1) that was significantly hypomethylated in severe periodontal disease compared with no/mild periodontal disease in European American participants. Higher methylation levels in a separate region in an unknown gene (located in Chr10: 743,992-744,958) was associated with significantly higher odds of edentulism compared with no/mild periodontal disease in African American participants. In subsequent CpG testing, four CpGs in a region previously associated with periodontitis located within HOXA4 were significantly hypermethylated in severe periodontal disease compared with no/mild periodontal disease in African American participants (odds ratio per 1 SD increase in methylation level: cg11015251: 1.28 (1.02, 1.61); cg14359292: 1.24 (1.01, 1.54); cg07317062: 1.30 (1.05, 1.61); cg08657492: 1.25 (1.01, 1.55)). CONCLUSIONS: Our study highlights epigenetic variations in ZPF57 and HOXA4 that are significantly and reproducibly associated with periodontitis. Future studies should evaluate gene regulatory mechanisms in the candidate regions of these loci.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

OBJECTIVE: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

Human cytomegalovirus alters immune cell profile with potential implications for patient survival in head and neck cancer.

Cytomegalovirus (CMV) is a highly prevalent human herpes virus that exerts a strong influence on immune repertoire which may influence cancer risk. We have tested whether CMV immunoglobulin G (IgG) serostatus is associated with immune cell proportions (n = 132 population controls), human papillomavirus (HPV) co-infection and head and neck cancer risk (n = 184 cancer cases and 188 controls) and patient survival. CMV status was not associated with the proportion of Natural Killer cells, B cells or the neutrophil-to-lymphocyte ratio. However, CD8+ T cells increased with increasing categories of IgG titers (P =1.7 × 10-10), and titers were inversely associated with the CD4:CD8 ratio (P = 5.6 × 10-5). Despite these differences in T cell proportions, CMV was not associated with HPV16 co-infection. CMV seropositivity was similar in cases (52%) and controls (47%) and was not associated with patient survival (hazard ratio [HR] 1.14, 95% confidence interval [CI]: 0.70 to 1.86). However, those patients with the highest titers had the worst survival (HR 1.91, 95% CI: 1.13 to 3.23). Tumor-based data from The Cancer Genome Atlas demonstrated that the presence of CMV transcripts was associated with worse patient survival (HR 1.79, 95% CI: 0.96 to 2.78). These findings confirm that a history of CMV infection alters T cell proportions, but this does not translate to HPV16 co-infection or head and neck cancer risk. Our data suggest that high titers and active CMV virus in the tumor environment may confer worse survival.

Proceedings of the fifth international Molecular Pathological Epidemiology (MPE) meeting.

Cancer heterogeneities hold the key to a deeper understanding of cancer etiology and progression and the discovery of more precise cancer therapy. Modern pathological and molecular technologies offer a powerful set of tools to profile tumor heterogeneities at multiple levels in large patient populations, from DNA to RNA, protein and epigenetics, and from tumor tissues to tumor microenvironment and liquid biopsy. When coupled with well-validated epidemiologic methodology and well-characterized epidemiologic resources, the rich tumor pathological and molecular tumor information provide new research opportunities at an unprecedented breadth and depth. This is the research space where Molecular Pathological Epidemiology (MPE) emerged over a decade ago and has been thriving since then. As a truly multidisciplinary field, MPE embraces collaborations from diverse fields including epidemiology, pathology, immunology, genetics, biostatistics, bioinformatics, and data science. Since first convened in 2013, the International MPE Meeting series has grown into a dynamic and dedicated platform for experts from these disciplines to communicate novel findings, discuss new research opportunities and challenges, build professional networks, and educate the next-generation scientists. Herein, we share the proceedings of the Fifth International MPE meeting, held virtually online, on May 24 and 25, 2021. The meeting consisted of 21 presentations organized into the three main themes, which were recent integrative MPE studies, novel cancer profiling technologies, and new statistical and data science approaches. Looking forward to the near future, the meeting attendees anticipated continuous expansion and fruition of MPE research in many research fronts, particularly immune-epidemiology, mutational signatures, liquid biopsy, and health disparities.

HiTIMED: hierarchical tumor immune microenvironment epigenetic deconvolution for accurate cell type resolution in the tumor microenvironment using tumor-type-specific DNA methylation data.

BACKGROUND: Cellular compositions of solid tumor microenvironments are heterogeneous, varying across patients and tumor types. High-resolution profiling of the tumor microenvironment cell composition is crucial to understanding its biological and clinical implications. Previously, tumor microenvironment gene expression and DNA methylation-based deconvolution approaches have been shown to deconvolve major cell types. However, existing methods lack accuracy and specificity to tumor type and include limited identification of individual cell types. RESULTS: We employed a novel tumor-type-specific hierarchical model using DNA methylation data to deconvolve the tumor microenvironment with high resolution, accuracy, and specificity. The deconvolution algorithm is named HiTIMED. Seventeen cell types from three major tumor microenvironment components can be profiled (tumor, immune, angiogenic) by HiTIMED, and it provides tumor-type-specific models for twenty carcinoma types. We demonstrate the prognostic significance of cell types that other tumor microenvironment deconvolution methods do not capture. CONCLUSION: We developed HiTIMED, a DNA methylation-based algorithm, to estimate cell proportions in the tumor microenvironment with high resolution and accuracy. HiTIMED deconvolution is amenable to archival biospecimens providing high-resolution profiles enabling to study of clinical and biological implications of variation and composition of the tumor microenvironment.

Physical activity modifies the relation between gestational perfluorooctanoic acid exposure and adolescent cardiometabolic risk.

OBJECTIVE: Exposure to per- and polyfluoroalkyl substances (PFAS) - endocrine disrupting chemicals - may increase cardiometabolic risk. We evaluated whether adolescent lifestyle factors modified associations between gestational PFAS exposure and cardiometabolic risk using a prospective cohort study. METHODS: In 166 mother-child pairs (HOME Study), we measured concentrations of four PFAS in maternal serum collected during pregnancy. When children were age 12 years, we calculated cardiometabolic risk scores from visceral adiposity area, blood pressure, and fasting serum biomarkers. We assessed adolescent physical activity and Healthy Eating Index scores using the Physical Activity Questionnaire for Older Children (PAQ-C), actigraphy, and 24-h diet recalls. Using multivariable linear regression and weighted quantile sum regression, we examined whether physical activity or diet modified covariate-adjusted associations of PFAS and their mixture with cardiometabolic risk scores. RESULTS: Physical activity modified associations between perfluorooctanoic acid (PFOA) and cardiometabolic risk scores. Each doubling of PFOA was associated with worse cardiometabolic risk scores among children with PAQ-C scores < median (ß:1.4; 95% CI:0.5, 2.2, n = 82), but not among those with PAQ-C scores ≥ median (ß: 0.2; 95% CI: 1.2, 0.7, n = 84) (interaction p-value = 0.01). Associations were most prominent for insulin resistance, leptin-adiponectin ratio, and visceral fat area. We observed results suggesting that physical activity modified the association of PFAS mixture with cardiometabolic risk scores, insulin resistance, and visceral fat area (interaction p-values = 0.17, 0.07, and 0.10, respectively); however, the 95% CIs of the interaction terms included the null value. We observed similar, but attenuated patterns for PFOA and actigraphy-based measures of physical activity. Diet did not modify any associations. Physical activity or diet did not modify associations for other PFAS. CONCLUSIONS: Childhood physical activity modified associations of prenatal serum PFOA concentrations with children's cardiometabolic risk in this cohort, indicating that lifestyle interventions may ameliorate the adverse effects of PFOA exposure.

Tracing human stem cell lineage during development using DNA methylation.

Stem cell maturation is a fundamental, yet poorly understood aspect of human development. We devised a DNA methylation signature deeply reminiscent of embryonic stem cells (a fetal cell origin signature, FCO) to interrogate the evolving character of multiple human tissues. The cell fraction displaying this FCO signature was highly dependent upon developmental stage (fetal versus adult), and in leukocytes, it described a dynamic transition during the first 5 yr of life. Significant individual variation in the FCO signature of leukocytes was evident at birth, in childhood, and throughout adult life. The genes characterizing the signature included transcription factors and proteins intimately involved in embryonic development. We defined and applied a DNA methylation signature common among human fetal hematopoietic progenitor cells and have shown that this signature traces the lineage of cells and informs the study of stem cell heterogeneity in humans under homeostatic conditions.

Gestational perfluoroalkyl substance exposure and body mass index trajectories over the first 12 years of life.

BACKGROUND/OBJECTIVES: Gestational exposure to perfluoroalkyl substances (PFAS), a ubiquitous class of persistent endocrine disrupting chemicals, is associated with increased risk of obesity and cardiometabolic disease. However, it is unclear if gestational PFAS exposure is associated with adiposity trajectories related to adult obesity and cardiometabolic health. SUBJECTS/METHODS: We measured perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid, and perfluorohexanesulfonic acid (PFHxS) concentrations in maternal serum collected between 16 weeks gestation and delivery in a cohort of 345 mother-child pairs in Cincinnati, OH (enrolled 2003-06). From age 4 weeks to 12 years, we measured weight and length or height up to eight times and calculated child body mass index (BMI) (1865 repeated measures). Using covariate-adjusted linear mixed models and splines to account for repeated BMI measures and nonlinear BMI patterns, respectively, we estimated the age/magnitude of infancy BMI zenith (~1 year) and childhood BMI nadir (~5 years), BMI accrual from 8 to 12 years, and BMI at age 12 years by PFAS terciles. RESULTS: BMI trajectories varied by PFOA concentrations (age × PFOA interaction p value = 0.03). Children born to women with higher PFOA concentrations had lower infancy and early childhood BMI, earlier BMI nadir, accelerating BMI gains in mid-childhood and adolescence, and higher BMI at age 12 years. Some of these associations were non-monotonic. PFOS and PFHxS were not associated with alterations in BMI trajectories, but were monotonically associated with lower BMI across infancy, childhood, and adolescence. Compared to children in the first PFOS tercile, those in the second (ß: -0.83; 95% confidence interval (CI): -2.11, 0.51 kg/m2), and third (ß: -1.41; 95% CI: -2.65, -0.14 kg/m2) had lower BMI at age 12 years. CONCLUSIONS: These results suggest that gestational PFOA exposure may be associated with BMI trajectories related to adult obesity and cardiometabolic disease, while PFOS and PFHxS exposure is associated with lower BMI in the first 12 years of life.

Placental gene networks at the interface between maternal PM2.5 exposure early in gestation and reduced infant birthweight.

BACKGROUND: A growing body of evidence links maternal exposure to particulate matter <2.5 µM in diameter (PM2.5) and deviations in fetal growth. Several studies suggest that the placenta plays a critical role in conveying the effects of maternal PM2.5 exposure to the developing fetus. These include observed associations between air pollutants and candidate placental features, such as mitochondrial DNA content, DNA methylation and telomere length. However, gaps remain in delineating the pathways linking the placenta to air pollution-related health effects, including a comprehensive profiling of placental processes impacted by maternal PM2.5 exposure. In this study, we examined alterations in a placental transcriptome-wide network in relation to maternal PM2.5 exposure prior to and during pregnancy and infant birthweight. METHODS: We evaluated PM2.5 exposure and placental RNA-sequencing data among study participants enrolled in the Rhode Island Child Health Study (RICHS). Daily residential PM2.5 levels were estimated using a hybrid model incorporating land-use regression and satellite remote sensing data. Distributed lag models were implemented to assess the impact on infant birthweight due to PM2.5 weekly averages ranging from 12 weeks prior to gestation until birth. Correlations were assessed between PM2.5 levels averaged across the identified window of susceptibility and a placental transcriptome-wide gene coexpression network previously generated using the WGCNA R package. RESULTS: We identified a sensitive window spanning 12 weeks prior to and 13 weeks into gestation during which maternal PM2.5 exposure is significantly associated with reduced infant birthweight. Two placental coexpression modules enriched for genes involved in amino acid transport and cellular respiration were correlated with infant birthweight as well as maternal PM2.5 exposure levels averaged across the identified growth restriction window. CONCLUSION: Our findings suggest that maternal PM2.5 exposure may alter placental programming of fetal growth, with potential implications for downstream health effects, including susceptibility to cardiometabolic health outcomes and viral infections.

DNA methylation in the adipose tissue and whole blood of Agent Orange-exposed Operation Ranch Hand veterans: a pilot study.

BACKGROUND: Between 1962 and 1971, the US Air Force sprayed Agent Orange across Vietnam, exposing many soldiers to this dioxin-containing herbicide. Several negative health outcomes have been linked to Agent Orange exposure, but data is lacking on the effects this chemical has on the genome. Therefore, we sought to characterize the impact of Agent Orange exposure on DNA methylation in the whole blood and adipose tissue of veterans enrolled in the Air Force Health Study (AFHS). METHODS: We received adipose tissue (n = 37) and whole blood (n = 42) from veterans in the AFHS. Study participants were grouped as having low, moderate, or high TCDD body burden based on their previously measured serum levels of dioxin. DNA methylation was assessed using the Illumina 450 K platform. RESULTS: Epigenome-wide analysis indicated that there were no FDR-significantly methylated CpGs in either tissue with TCDD burden. However, 3 CpGs in the adipose tissue (contained within SLC9A3, LYNX1, and TNRC18) were marginally significantly (q < 0.1) hypomethylated, and 1 CpG in whole blood (contained within PTPRN2) was marginally significantly (q < 0.1) hypermethylated with high TCDD burden. Analysis for differentially methylated DNA regions yielded SLC9A3, among other regions in adipose tissue, to be significantly differentially methylated with higher TCDD burden. Comparing whole blood data to a study of dioxin exposed adults from Alabama identified a CpG within the gene SMO that was hypomethylated with dioxin exposure in both studies. CONCLUSION: We found limited evidence of dioxin associated DNA methylation in adipose tissue and whole blood in this pilot study of Vietnam War veterans. Nevertheless, loci in the genes of SLC9A3 in adipose tissue, and PTPRN2 and SMO in whole blood, should be included in future exposure analyses.

Leveraging cell-specific differentially methylated regions to identify leukocyte infiltration in adipose tissue.

Obesity is understood to be an inflammatory condition characterized in part by changes in resident immune cell populations in adipose tissue. However, much of this knowledge has been obtained through experimental animal models. Epigenetic mechanisms, such as DNA methylation may be useful tools for characterizing the changes in immune cell populations in human subjects. In this study, we introduce a simple and intuitive method for assessing cellular infiltration by blood into other heterogeneous, admixed tissues such as adipose tissue, and apply this approach in a large human cohort study. Associations between higher leukocyte infiltration, measured by evaluating a distance measure between the methylation signatures of leukocytes and adipose tissue, and increasing body mass index (BMI) or android fat mass (AFM) were identified and validated in independent replication samples for CD4 (pBMI = 0.009, pAFM = 0.020), monocytes (pBMI = 0.001, pAFM = 4.3 × 10-4 ), and dendritic cells (pBMI = 0.571, pAFM = 0.012). Patterns of depletion with increasing adiposity were observed for plasma B (pBMI = 0.430, pAFM = 0.004) and immature B (pBMI = 0.022, pAFM = 0.042) cells. CD4, dendritic, monocytes, immature B, and plasma B cells may be important agents in the inflammatory process. Finally, the method used to assess leukocyte infiltration in this study is straightforwardly extended to other cell types and tissues in which infiltration might be of interest.

Risk Prediction Models for Head and Neck Cancer in the US Population From the INHANCE Consortium.

Head and neck cancer (HNC) risk prediction models based on risk factor profiles have not yet been developed. We took advantage of the large database of the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, including 14 US studies from 1981-2010, to develop HNC risk prediction models. Seventy percent of the data were used to develop the risk prediction models; the remaining 30% were used to validate the models. We used competing-risk models to calculate absolute risks. The predictors included age, sex, education, race/ethnicity, alcohol drinking intensity, cigarette smoking duration and intensity, and/or family history of HNC. The 20-year absolute risk of HNC was 7.61% for a 60-year-old woman who smoked more than 20 cigarettes per day for over 20 years, consumed 3 or more alcoholic drinks per day, was a high school graduate, had a family history of HNC, and was non-Hispanic white. The 20-year risk for men with a similar profile was 6.85%. The absolute risks of oropharyngeal and hypopharyngeal cancers were generally lower than those of oral cavity and laryngeal cancers. Statistics for the area under the receiver operating characteristic curve (AUC) were 0.70 or higher, except for oropharyngeal cancer in men. This HNC risk prediction model may be useful in promoting healthier behaviors such as smoking cessation or in aiding persons with a family history of HNC to evaluate their risks.

Dietary glycaemic index, glycaemic load and head and neck cancer risk: a pooled analysis in an international consortium.

High dietary glycaemic index (GI) and glycaemic load (GL) may increase cancer risk. However, limited information was available on GI and/or GL and head and neck cancer (HNC) risk. We conducted a pooled analysis on 8 case-control studies (4081 HNC cases; 7407 controls) from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) of HNC, and its subsites, from fixed- or mixed-effects logistic models including centre-specific quartiles of GI or GL. GI, but not GL, had a weak positive association with HNC (ORQ4 vs. Q1 = 1.16; 95% CI = 1.02-1.31). In subsites, we found a positive association between GI and laryngeal cancer (ORQ4 vs. Q1 = 1.60; 95% CI = 1.30-1.96) and an inverse association between GL and oropharyngeal cancer (ORQ4 vs. Q1 = 0.78; 95% CI = 0.63-0.97). This pooled analysis indicates a modest positive association between GI and HNC, mainly driven by laryngeal cancer.

Chrysotile fibers in tissue adjacent to laryngeal squamous cell carcinoma in cases with a history of occupational asbestos exposure.

Asbestos describes a group of naturally occurring fibrous silicate mineral compounds that have been associated with a number of respiratory maladies, including mesothelioma and lung cancer. In addition, based primarily on epidemiologic studies, asbestos has been implicated as a risk factor for laryngeal and pharyngeal squamous cell carcinoma (SCC). The main objective of this work was to strengthen existing evidence via empirical demonstration of persistent asbestos fibers embedded in the tissue surrounding laryngeal and pharyngeal SCC, thus providing a more definitive biological link between exposure and disease. Six human papillomavirus (HPV)-negative laryngeal (n = 4) and pharyngeal (n = 2) SCC cases with a history working in an asbestos-exposed occupation were selected from a large population-based case-control study of head and neck cancer. A laryngeal SCC case with no history of occupational asbestos exposure was included as a control. Tissue cores were obtained from adjacent nonneoplastic tissue in tumor blocks from the initial primary tumor resection, and mineral fiber analysis was performed using a scanning electron microscope equipped with an energy dispersive X-ray analyzer (EDXA). Chrysotile asbestos fiber bundles were identified in 3/6 of evaluated cases with a history of occupational asbestos exposure. All three cases had tumors originating in the larynx. In addition, a wollastonite fiber of unclear significance was identified one of the HPV-negative pharyngeal SCC cases. No mineral fibers were identified in adjacent tissue of the case without occupational exposure. The presence of asbestos fibers in the epithelial tissue surrounding laryngeal SCC in cases with a history of occupational asbestos exposure adds a key line of physical evidence implicating asbestos as an etiologic factor.

Mediation by differential DNA methylation of known associations between single nucleotide polymorphisms and bladder cancer risk.

BACKGROUND: Though bladder cancer has been the subject of many well-powered genome-wide association studies, the mechanisms involving bladder-cancer-associated single nucleotide polymorphisms (SNPs) remain largely unknown. This study focuses on rs798766, rs401681, rs2294008, and rs8102137, which have been associated with bladder cancer and are also cis-acting methylation quantitative loci (mQTL). METHODS: Among 412 bladder cancer cases and 424 controls from the Women's Health Initiative (WHI), we assessed whether the effects of these SNPs on bladder cancer are mediated through proximal DNA methylation changes in pre-diagnostic blood at mQTL-associated CpG sites, which we refer to as natural indirect effects (NIEs). We used a multiple-mediator mediation model for each of the four mQTL adjusted for matching variables and potential confounders, including race/ethnicity, smoking status, and pack-years of smoking. RESULTS: While not statistically significant, our results suggest that substantial proportions of the modest effects of rs401681 (ORNIE = 1.05, 95% confidence interval (CI) = 0.89 to 1.25; NIE percent = 98.5%) and rs2294008 (ORNIE = 1.10, 95% CI = 0.90 to 1.33; NIE percent = 77.6%) on bladder cancer risk are mediated through differential DNA methylation at nearby mQTL-associated CpG sites. The suggestive results indicate that rs2294008 may affect bladder cancer risk through a set of genes in the lymphocyte antigen 6 family, which involves genes that bind to and modulate nicotinic acetylcholine receptors. There was no suggestive evidence supporting mediation for rs8102137 and rs798766. CONCLUSIONS: Though larger studies are necessary, the methylation changes associated with rs401681 and rs2294008 at mQTL-associated CpG sites may be relevant for bladder carcinogenesis, and this study demonstrates how multi-omic data can be integrated to help understand the downstream effects of genetics variants.

A Bayesian framework for identifying consistent patterns of microbial abundance between body sites.

Recent studies have found that the microbiome in both gut and mouth are associated with diseases of the gut, including cancer. If resident microbes could be found to exhibit consistent patterns between the mouth and gut, disease status could potentially be assessed non-invasively through profiling of oral samples. Currently, there exists no generally applicable method to test for such associations. Here we present a Bayesian framework to identify microbes that exhibit consistent patterns between body sites, with respect to a phenotypic variable. For a given operational taxonomic unit (OTU), a Bayesian regression model is used to obtain Markov-Chain Monte Carlo estimates of abundance among strata, calculate a correlation statistic, and conduct a formal test based on its posterior distribution. Extensive simulation studies demonstrate overall viability of the approach, and provide information on what factors affect its performance. Applying our method to a dataset containing oral and gut microbiome samples from 77 pancreatic cancer patients revealed several OTUs exhibiting consistent patterns between gut and mouth with respect to disease subtype. Our method is well powered for modest sample sizes and moderate strength of association and can be flexibly extended to other research settings using any currently established Bayesian analysis programs.

Exposure to Per- and Polyfluoroalkyl Substances and Adiposity at Age 12 Years: Evaluating Periods of Susceptibility.

Per- and polyfluoroalkyl substances (PFAS) exposure may increase adiposity and obesity risk in children. However, no studies have extended these findings into adolescence or identified periods of heightened susceptibility. We estimated associations of repeated pre- and postnatal serum PFAS concentrations with adolescent adiposity and risk of overweight/obesity. We studied 212 mother-offspring pairs from the HOME Study. We quantified serum concentrations of four PFAS in mothers at ∼16 week gestation and their children at birth and ages 3, 8, and 12 years. We assessed adiposity at 12 years using anthropometry and dual-energy X-ray absorptiometry. Using multiple informant models, we estimated covariate-adjusted associations of an interquartile range (IQR) increase in log2-transformed PFAS for each time period with adiposity measures and tested differences in these associations. Serum perfluorooctanoate (PFOA) and perfluorohexane sulfonate (PFHxS) concentrations during pregnancy were associated with modest increases in central adiposity and risk of overweight/obesity, but there was no consistent pattern for postnatal concentrations. We observed nonlinear associations between PFOA in pregnancy and some measures of adiposity. Overall, we observed a pattern of modest positive associations of gestational PFOA and PFHxS concentrations with central adiposity and the risk of obesity in adolescents, while no pattern was observed for postnatal PFAS concentrations.

Firefighter occupation is associated with increased risk for laryngeal and hypopharyngeal squamous cell carcinoma among men from the Greater Boston area.

OBJECTIVE: Firefighters are exposed to a wide variety of carcinogens during the line of duty, including several associated with head and neck cancer. Existing studies assessing head and neck cancer risk with firefighting have predominately included occupational cohorts or registry data, which are limited by inability to adjust for smoking and alcohol consumption-major risk factors for head and neck cancer. Our objective was to assess the risk of head and neck cancer among men with an occupational history as a firefighter. METHODS: This work was conducted using male subjects from a large population-based case-control study of head and neck cancer from the greater Boston area using self-reported occupational history (718 cases and 905 controls). RESULTS: An occupational history as a firefighter was reported for 11 cases and 14 controls. Although no significant association was observed overall, we observed substantial increased risk for hypopharyngeal and laryngeal squamous cell carcinoma among professional municipal firefighters who had a light or no smoking history (OR=8.06, 95% CI 1.74 to 37.41), with significantly increasing risk per decade as a firefighter (OR=2.10, 95% CI 1.06 to 4.14). CONCLUSION: Professional municipal firefighters may be at increased risk for hypopharyngeal and laryngeal squamous cell carcinoma due to carcinogenic exposures encountered during the line of duty.