DNA Methylation-Derived Immune Cell Proportions and Cancer Risk, Including Lung Cancer, in Black Participants.

Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation obscures vital insights into how cancer risk varies across race. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers from blood samples collected at baseline on participants without cancer in the Atherosclerosis Risk in Communities (ARIC) Study. Over a mean of 17.5 years of follow-up, 668 incident cancers were diagnosed in 2,467 Black participants. Cox proportional hazards regression was used to examine immune cell subtype proportions and overall cancer incidence and site-specific incidence (lung, breast, and prostate cancers). Higher T regulatory cell proportions were associated with statistically significantly higher lung cancer risk (hazard ratio = 1.22, 95% confidence interval = 1.06-1.41 per percent increase). Increased memory B cell proportions were associated with significantly higher risk of prostate cancer (1.17, 1.04-1.33) and all cancers (1.13, 1.05-1.22). Increased CD8+ naïve cell proportions were associated with significantly lower risk of all cancers in participants ≥55 years (0.91, 0.83-0.98). Other immune cell subtypes did not display statistically significant associations with cancer risk. These results in Black participants align closely with prior findings in largely White populations. Findings from this study could help identify those at high cancer risk and outline risk stratifying to target patients for cancer screening, prevention, and other interventions. Further studies should assess these relationships in other cancer types, better elucidate the interplay of B cells in cancer risk, and identify biomarkers for personalized risk stratification.

Microbial butyrate capacity is reduced in inflamed mucosa in patients with ulcerative colitis.

Reduced butyrate-production capacity has been reported in fecal microbial communities in patients with active ulcerative colitis. However, the butyrate-production capacity of the mucosal microbiome from active vs quiescent mucosa in ulcerative colitis has been unexplored. We sought to determine the diversity and relative abundance of mucosal bacterial and fungal communities from endoscopically active vs quiescent mucosa in patients with UC, and aimed to predict contributions of mucosal microbial communities to butyrate synthesis. Systematic, segmental right- and left-sided biopsies were obtained from endoscopically active (n = 13) or quiescent (n = 17) colonic mucosa, among 15 patients with pan-colonic ulcerative colitis. Dietary fiber intake of patients was performed using the validated five-item FiberScreen questionnaire. Amplicon sequencing of mucosal bacteria and fungi was performed. The diversity and relative abundance of mucosal bacterial and fungal taxa were quantified, and predicted contributions to butyrate synthesis were ascertained. Bacterial alpha and beta diversity were similar between active vs quiescent mucosa. Butyrogenic taxa were significantly increased in quiescence, including Butyricimonas, Subdoligranulum, and Alistipes. Predicted butyrate kinase activity was significantly and concomitantly increased in quiescent mucosa. Fiber intake was positively correlated with butyrogenic microbes. Compared to mucosal bacterial prevalence, mucosal fungi were detected in low prevalence. Butyrogenic microbes are relatively increased in quiescent mucosa in ulcerative colitis, and may be related to increased fiber intake during quiescence. Manipulation of the mucosal microbiome towards butyrate-producing bacteria may be associated with endoscopic quiescence.

Dynamics of the Gut Mycobiome in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Intestinal fungi have been implicated in the pathogenesis of ulcerative colitis (UC). However, it remains unclear if fungal composition is altered during active versus quiescent disease. METHODS: We analyzed clinical and metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD), available via the IBD Plexus Program of the Crohn's & Colitis Foundation. We evaluated the fungal composition of fecal samples from 421 patients with UC during clinical activity and remission. Within a longitudinal subcohort (n = 52), we assessed for dynamic taxonomic changes across alterations in clinical activity over time. We examined if fungal amplicon sequence variants and fungal-bacterial relationships were altered during activity versus remission. Finally, we classified activity in UC using a supervised machine learning random forest model trained on fungal abundance data. RESULTS: During clinical activity, the relative abundance of genus Candida was increased 3.5-fold (P-adj < 1 × 10-4) compared with during remission. Patients with longitudinal reductions in clinical activity demonstrated parallel reductions in Candida relative abundance (P < .05). Candida relative abundance correlated with Parabacteroides diastonis, Faecalibacterium prausnitzii, and Bacteroides dorei relative abundance (P < .05) during remission; however, these correlations were disrupted during activity. Fungal abundance data successfully classified patients with active or quiescent UC (area under the curve ∼0.80), with Candida relative abundance critical to the success of the model. CONCLUSIONS: Clinical activity in UC is associated with an increased relative abundance of Candida, cross-sectionally and dynamically over time. The role of fecal Candida as a target for therapeutics in UC should be evaluated.

Periodontitis and risk of cancer: Mechanistic evidence.

This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low-grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro-aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non-indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor-associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor-infiltrating T cells) and the increased expression of pro-inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Methylomic, Proteomic, and Metabolomic Correlates of Traffic-Related Air Pollution in the Context of Cardiorespiratory Health: A Systematic Review, Pathway Analysis, and Network Analysis.

A growing body of literature has attempted to characterize how traffic-related air pollution (TRAP) affects molecular and subclinical biological processes in ways that could lead to cardiorespiratory disease. To provide a streamlined synthesis of what is known about the multiple mechanisms through which TRAP could lead to cardiorespiratory pathology, we conducted a systematic review of the epidemiological literature relating TRAP exposure to methylomic, proteomic, and metabolomic biomarkers in adult populations. Using the 139 papers that met our inclusion criteria, we identified the omic biomarkers significantly associated with short- or long-term TRAP and used these biomarkers to conduct pathway and network analyses. We considered the evidence for TRAP-related associations with biological pathways involving lipid metabolism, cellular energy production, amino acid metabolism, inflammation and immunity, coagulation, endothelial function, and oxidative stress. Our analysis suggests that an integrated multi-omics approach may provide critical new insights into the ways TRAP could lead to adverse clinical outcomes. We advocate for efforts to build a more unified approach for characterizing the dynamic and complex biological processes linking TRAP exposure and subclinical and clinical disease and highlight contemporary challenges and opportunities associated with such efforts.

Methylomic, proteomic, and metabolomic correlates of traffic-related air pollution: A systematic review, pathway analysis, and network analysis relating traffic-related air pollution to subclinical and clinical cardiorespiratory outcomes.

A growing body of literature has attempted to characterize how traffic-related air pollution (TRAP) affects molecular and subclinical biological processes in ways that could lead to cardiorespiratory disease. To provide a streamlined synthesis of what is known about the multiple mechanisms through which TRAP could lead cardiorespiratory pathology, we conducted a systematic review of the epidemiological literature relating TRAP exposure to methylomic, proteomic, and metabolomic biomarkers in adult populations. Using the 139 papers that met our inclusion criteria, we identified the omic biomarkers significantly associated with short- or long-term TRAP and used these biomarkers to conduct pathway and network analyses. We considered the evidence for TRAP-related associations with biological pathways involving lipid metabolism, cellular energy production, amino acid metabolism, inflammation and immunity, coagulation, endothelial function, and oxidative stress. Our analysis suggests that an integrated multi-omics approach may provide critical new insights into the ways TRAP could lead to adverse clinical outcomes. We advocate for efforts to build a more unified approach for characterizing the dynamic and complex biological processes linking TRAP exposure and subclinical and clinical disease, and highlight contemporary challenges and opportunities associated with such efforts.

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.

Alterations in the Fungal Microbiome in Ulcerative Colitis.

BACKGROUND: Although gut fungi have been implicated in the immunopathogenesis of inflammatory bowel disease, the fungal microbiome has not been deeply explored across endohistologic activity and treatment exposure in ulcerative colitis. METHODS: We analyzed data from the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry. We evaluated the fungal composition of fecal samples from 98 patients with ulcerative colitis across endoscopic activity (n = 43), endohistologic activity (n = 41), and biologic exposure (n = 82). Across all subgroups, we assessed fungal diversity and differential abundance of taxonomic groups. RESULTS: We identified 500 unique fungal amplicon sequence variants across the cohort of 82 patients, dominated by phylum Ascomycota. Compared with endoscopic remission, patients with endoscopic activity had increased Saccharomyces (log2 fold change = 4.54; adjusted P < 5 × 10-5) and increased Candida (log2 fold change = 2.56; adjusted P < .03). After adjusting for age, sex, and biologic exposure among patients with endoscopic activity, Saccharomyces (log2 fold change = 7.76; adjusted P < 1 × 10-15) and Candida (log2 fold change = 7.28; adjusted P< 1 × 10-8) remained enriched during endoscopic activity compared with quiescence. CONCLUSIONS: Endoscopic inflammation in ulcerative colitis is associated with an expansion of Saccharomyces and Candida compared with remission. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in ulcerative colitis should be evaluated.

Gut fungi have been implicated in the pathogenesis of ulcerative colitis. In this retrospective study utilizing deep sequencing of the fecal fungal microbiome, Saccharomyces and Candida were increased during endoscopic inflammation and Penicillium was increased during endoscopic remission.

What is the cost-effectiveness of menu calorie labelling on reducing obesity-associated cancer burdens? An economic evaluation of a federal policy intervention among 235 million adults in the USA.

OBJECTIVE: To assess the impact of menu calorie labelling on reducing obesity-associated cancer burdens in the USA. DESIGN: Cost-effectiveness analysis using a Markov cohort state-transition model. SETTING: Policy intervention. PARTICIPANTS: A modelled population of 235 million adults aged ≥20 years in 2015-2016. INTERVENTIONS: The impact of menu calorie labelling on reducing 13 obesity-associated cancers among US adults over a lifetime was evaluated for: (1) effects on consumer behaviours; and (2) additional effects on industry reformulation. The model integrated nationally representative demographics, calorie intake from restaurants, cancer statistics and estimates on associations of policy with calorie intake, dietary change with body mass index (BMI) change, BMI with cancer rates, and policy and healthcare costs from published literature. MAIN OUTCOME MEASURES: Averted new cancer cases and cancer deaths and net costs (in 2015 US$) among the total population and demographic subgroups were determined. Incremental cost-effectiveness ratios from societal and healthcare perspectives were assessed and compared with the threshold of US$150 000 per quality-adjusted life year (QALY) gained. Probabilistic sensitivity analyses incorporated uncertainty in input parameters and generated 95% uncertainty intervals (UIs). RESULTS: Considering consumer behaviour alone, this policy was associated with 28 000 (95% UI 16 300 to 39 100) new cancer cases and 16 700 (9610 to 23 600) cancer deaths averted, 111 000 (64 800 to 158 000) QALYs gained, and US$1480 (884 to 2080) million saved in cancer-related medical costs among US adults. The policy was associated with net cost savings of US$1460 (864 to 2060) million and US$1350 (486 to 2260) million from healthcare and societal perspectives, respectively. Additional industry reformulation would substantially increase policy impact. Greater health gains and cost savings were predicted among young adults, Hispanic and non-Hispanic Black individuals. CONCLUSIONS: Study findings suggest that menu calorie labelling is associated with lower obesity-related cancer burdens and reduced healthcare costs. Policymakers may prioritise nutrition policies for cancer prevention in the USA.

Circulating IgG antibodies to periodontal bacteria and lung cancer risk in the CLUE cohorts.

BACKGROUND: Oral health is a key indicator of overall health, well-being, and quality of life. Several studies have provided new evidence about the role of oral diseases, specifically periodontitis, in generating risk for various forms of cancers, including lung, colorectal, and pancreatic cancers. METHODS: Incident lung cancer cases (n = 192) and matched controls (n = 192) were selected from participants of the CLUE I and CLUE II cohorts. Archived serum samples collected from participants in 1974 (in CLUE I) were analyzed using immunoblotting for immunoglobulin G (IgG) antibody levels to 13 bacteria of the periodontium. Associations between antibody levels and lung cancer were estimated using conditional logistic regression. RESULTS: Most of the periodontal bacterial antibodies measured were inversely associated with lung cancer risk; of these, 3 were statistically significant (Prevotellaintermedia, Actinomyces naeslundii, and Veillonella parvula). A statistically significant positive association was observed for one of the Porphyromonas gingivalis strains after adjusting for P. intermedia. The sum of the logarithm of antibodies against the 13 measured bacteria was inversely associated with risk of lung cancer when the analysis was restricted to a longer follow-up (31-44 years after blood collection, highest vs lowest quartile: odds ratio = 0.26, 95% confidence interval = 0.08 to 0.84). CONCLUSIONS: Findings from this study highlight the complexity of using serum IgG antibodies to periodontal bacteria to identify associations between oral pathogens and risk of lung cancer. The inverse associations observed for antibodies to periodontal bacteria suggest that these may represent markers of immunity that provide some advantage in reducing the development of lung cancer.

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.

Epigenetic age and lung cancer risk in the CLUE II prospective cohort study.

BACKGROUND: Epigenetic age, a robust marker of biological aging, has been associated with obesity, low-grade inflammation and metabolic diseases. However, few studies have examined associations between different epigenetic age measures and risk of lung cancer, despite great interest in finding biomarkers to assist in risk stratification for lung cancer screening. METHODS: A nested case-control study of lung cancer from the CLUE II cohort study was conducted using incidence density sampling with 1:1 matching of controls to lung cancer cases (n = 208 matched pairs). Prediagnostic blood samples were collected in 1989 (CLUE II study baseline) and stored at -70°C. DNA was extracted from buffy coat and DNA methylation levels were measured using Illumina MethylationEPIC BeadChip Arrays. Three epigenetic age acceleration (i.e., biological age is greater than chronological age) measurements (Horvath, Hannum and PhenoAge) were examined in relation to lung cancer risk using conditional logistic regression. RESULTS: We did not observe associations between the three epigenetic age acceleration measurements and risk of lung cancer overall; however, inverse associations for the two Hannum age acceleration measures (intrinsic and extrinsic) were observed in men and among younger participants, but not in women or older participants. We did not observe effect modification by time from blood draw to diagnosis. CONCLUSION: Findings from this study do not support a positive association between three different biological age acceleration measures and risk of lung cancer. Additional studies are needed to address whether epigenetic age is associated with lung cancer in never smokers.

Factors associated with suspected nonmelanoma skin cancers, dysplastic nevus, and cutaneous melanoma among first-time SpotMe screening program participants during 2009-2010.

BACKGROUND: There have been no studies of the American Academy of Dermatology's SpotMe skin cancer screening program to collectively analyze and determine the factors associated with suspected basal cell carcinoma (BCC), squamous cell carcinoma (SCC), dysplastic nevus (DN), and cutaneous melanoma (CM) diagnoses. OBJECTIVE: Describe the demographics, risk factors, and access to care profiles associated with suspected diagnoses of BCC, SCC, DN, and CM among first-time SpotMe screenees during 2009-2010. METHODS: We conducted a cross-sectional analysis of data from the SpotMe skin cancer screenings conducted in 2009 and 2010. We performed multivariable logistic regression analysis for each diagnosis, incorporating standard demographic, access to care, and risk factor variables in the models. RESULTS: Men, those without a regular dermatologist, persons reporting recently changing moles, and those with a personal history of melanoma were at increased risk for each of the suspected diagnoses analyzed. Uninsured persons were at increased risk for suspected malignancies (BCC, SCC, and CM). LIMITATIONS: Lack of histologic confirmation for diagnoses and cross-sectional design. CONCLUSION: Among first-time SpotMe participants, suspected diagnoses of BCC, SCC, DN, and CM shared several associated factors, which may be considered when planning outreach and screening for populations at risk for skin cancer.

Periodontal and Other Oral Bacteria and Risk of Lung Cancer in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Evidence suggests that periodontal disease is associated with increased lung cancer risk, but whether periodontal pathogens are explanatory is unknown. We prospectively studied associations of prediagnostic circulating antibodies with oral bacteria and of periodontal bacteria in subgingival plaque with lung cancer. METHODS: We included 4,263 cancer-free participants in the Atherosclerosis Risk in Communities study with previously measured serum IgG antibodies to 18 oral bacteria. In 1,287 participants for whom subgingival plaque was collected, counts for 8 periodontal bacteria were previously measured. Incident lung cancers (N = 118) were ascertained through 2015 (median follow-up = 17.5 years). We used Cox regression to estimate multivariable-adjusted associations, including for sums of antibodies to orange (C. rectus, F. nucleatum, P. intermedia, P. micra, and P. nigrescens) and red (P. gingivalis, T. forsythensis, and T. denticola) complex bacteria. RESULTS: Orange complex bacteria antibodies were positively associated with lung cancer [per IQR hazard ratios (HR) = 1.15; 95% confidence intervals (CI), 1.02-1.29], which was stronger in men (HR = 1.27, 95% CI 1.08-1.49), and explained by P. intermedia and P. nigrescens (HR = 1.15; 95% CI, 1.04-1.26). Suggestive positive associations with lung cancer (N = 40) were observed for F. nucleatum, A. actinomycetemcomitans, and P. gingivalis counts. Significant positive associations were found for the count to antibody ratio for P. intermedia and P. gingivalis. CONCLUSIONS: We identified positive associations with lung cancer for oral bacteria, especially orange complex that are moderately pathogenic for periodontal disease. IMPACT: This prospective study supports the need for more research on periodontal bacteria in lung cancer etiology. If associations are supported, this may inform novel lung cancer prevention strategies.

Tooth count, untreated caries and mortality in US adults: a population-based cohort study.

BACKGROUND: The link between oral diseases and mortality remains under-explored. We aimed to evaluate the associations between tooth count, untreated caries and risk of all-cause and cause-specific mortality. METHODS: Data on 24 029 adults from the National Health and Nutrition Examination Survey 1988-94/1999-2010, with mortality linkage to the National Death Index to 31 December 2015, were analysed. Baseline total number of permanent teeth and any untreated caries were assessed by trained dental professionals. RESULTS: During up to 27 years of follow-up, 5270 deaths occurred. Fewer permanent teeth were associated with higher all-cause mortality, including heart disease and cancer mortality (all P <0.05 for trend) but not cerebrovascular disease mortality. For every 10 teeth missing, the multivariable-adjusted hazard ratios (HRs) were 1.13 (95% CI: 1.08 to 1.18) for all-cause, 1.16 (95% CI: 1.05, 1.29) for heart disease and 1.19 (95% CI: 1.09, 1.29) for cancer mortality. Untreated caries was associated with increased all-cause (HR: 1.26, 95% CI: 1.15, 1.39) and heart disease mortality (HR: 1.48, 95% CI: 1.17, 1.88) but not cerebrovascular disease/cancer mortality, after adjusting for tooth count, periodontitis and sociodemographic/lifestyle factors. Compared with those without untreated caries and with 25-28 teeth, individuals with untreated caries and 1-16 teeth had a 53% increased risk of all-cause mortality (HR: 1.53, 95% CI: 1.27, 1.85) and 96 % increased risk of heart disease mortality (HR: 1.96, 95% CI: 1.28, 3.01). CONCLUSIONS: In nationally representative cohorts, fewer permanent teeth and untreated caries were associated with all-cause and heart disease mortality. Fewer teeth were also associated with higher cancer mortality.

The oral microbiome in relation to pancreatic cancer risk in African Americans.

BACKGROUND: African Americans have the highest pancreatic cancer incidence of any racial/ethnic group in the United States. The oral microbiome was associated with pancreatic cancer risk in a recent study, but no such studies have been conducted in African Americans. Poor oral health, which can be a cause or effect of microbial populations, was associated with an increased risk of pancreatic cancer in a single study of African Americans. METHODS: We prospectively investigated the oral microbiome in relation to pancreatic cancer risk among 122 African-American pancreatic cancer cases and 354 controls. DNA was extracted from oral wash samples for metagenomic shotgun sequencing. Alpha and beta diversity of the microbial profiles were calculated. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between microbes and pancreatic cancer risk. RESULTS: No associations were observed with alpha or beta diversity, and no individual microbial taxa were differentially abundant between cases and control, after accounting for multiple comparisons. Among never smokers, there were elevated ORs for known oral pathogens: Porphyromonas gingivalis (OR = 1.69, 95% CI: 0.80-3.56), Prevotella intermedia (OR = 1.40, 95% CI: 0.69-2.85), and Tannerella forsythia (OR = 1.36, 95% CI: 0.66-2.77). CONCLUSIONS: Previously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.

Epigenome-wide scan identifies differentially methylated regions for lung cancer using pre-diagnostic peripheral blood.

BACKGROUND: DNA methylation markers have been associated with lung cancer risk and may identify aetiologically relevant genomic regions, or alternatively, be markers of disease risk factors or biological processes associated with disease development. METHODS: In a nested case-control study, we measured blood leukocyte DNA methylation levels in pre-diagnostic samples collected from 430 participants (208 cases; 222 controls) in the 1989 CLUE II cohort. We compared DNA methylation levels with case/control status to identify novel genomic regions, both single CpG sites and differentially methylated regions (DMRs), while controlling for known DNA methylation changes associated with smoking using a previously described pack-years-based smoking methylation score. Stratification analyses were conducted over time from blood draw to diagnosis, histology, and smoking status. RESULTS: We identified 16 single CpG sites and 40 DMRs significantly associated with lung cancer risk (q < 0.05). The identified genomic regions were associated with genes including H19, HOXA3/HOXA4, RUNX3, BRICD5, PLXNB2, and RP13. For the single CpG sites, the strongest association was noted for cg09736286 in the DIABLO gene (OR [for 1 SD] = 2.99, 95% CI: 1.95-4.59, P-value = 4.81 × 10-7). We found that CpG sites in the HOXA3/HOXA4 region were hypermethylated in cases compared to controls. CONCLUSION: The single CpG sites and DMRs that we identified represented significant measurable differences in lung cancer risk, providing potential biomarkers for lung cancer risk stratification. Future studies will need to examine whether these regions are causally related to lung cancer.

Methylation-derived inflammatory measures and lung cancer risk and survival.

BACKGROUND: Examining immunity-related DNA methylation alterations in blood could help elucidate the role of the immune response in lung cancer etiology and aid in discovering factors that are key to lung cancer development and progression. In a nested, matched case-control study, we estimated methylation-derived NLR (mdNLR) and quantified DNA methylation levels at loci previously linked with circulating concentrations of C-reactive protein (CRP). We examined associations between these measures and lung cancer risk and survival. RESULTS: Using conditional logistic regression and further adjusting for BMI, batch effects, and a smoking-based methylation score, we observed a 47% increased risk of non-small cell lung cancer (NSCLC) for one standard deviation (SD) increase in mdNLR (n = 150 pairs; OR: 1.47, 95% CI 1.08, 2.02). Using a similar model, the estimated CRP Scores were inversely associated with risk of NSCLC (e.g., Score 1 OR: 0.57, 95% CI: 0.40, 0.81). Using Cox proportional hazards models adjusting for age, sex, smoking status, methylation-predicted pack-years, BMI, batch effect, and stage, we observed a 28% increased risk of dying from lung cancer (n = 145 deaths in 205 cases; HR: 1.28, 95% CI: 1.09, 1.50) for one SD increase in mdNLR. CONCLUSIONS: Our study demonstrates that immunity status measured with DNA methylation markers is associated with lung cancer a decade or more prior to cancer diagnosis. A better understanding of immunity-associated methylation-based biomarkers in lung cancer development could provide insight into critical pathways.

DNA Methylation in Peripheral Blood: Providing Novel Biomarkers of Exposure and Immunity to Examine Cancer Risk.

DNA methylation is an epigenetic phenomenon that can alter and control gene expression. Because methylation plays a key role in cell differentiation, methylation markers have been identified that are unique to a given cell type; these markers are stable and can be measured in tissue or whole blood. The article by Katzke and colleagues, published in this issue, uses methylation markers to estimate proportions of immune cell subtypes in peripheral blood samples that were collected prior to diagnosis, thus allowing them to directly examine associations with pancreatic cancer risk. Given that immune-cell counts cannot be measured from archived blood, and that retrospective case-control studies rely on blood that is collected after cancer diagnosis, few studies have been able to examine the role of the systemic immune response in cancer risk. Measurement of DNA methylation in peripheral blood, primarily through development of whole-genome approaches, has also opened new doors to examining cancer etiology.See related article by Katzke et al., p. 2179.

Disparities in Health and Economic Burdens of Cancer Attributable to Suboptimal Diet in the United States, 2015‒2018.

Objectives. To quantify disparities in health and economic burdens of cancer attributable to suboptimal diet among US adults. Methods. Using a probabilistic cohort state-transition model, we estimated the number of new cancer cases and cancer deaths, and economic costs of 15 diet-related cancers attributable to suboptimal intake of 7 dietary factors (a low intake of fruits, vegetables, dairy, and whole grains and a high intake of red and processed meats and sugar-sweetened beverages) among a closed cohort of US adults starting in 2017. Results. Suboptimal diet was estimated to contribute to 3.04 (95% uncertainty interval [UI] = 2.88, 3.20) million new cancer cases, 1.74 (95% UI = 1.65, 1.84) million cancer deaths, and $254 (95% UI = $242, $267) billion economic costs among US adults aged 20 years or older over a lifetime. Diet-attributable cancer burdens were higher among younger adults, men, non-Hispanic Blacks, and individuals with lower education and income attainments than other population subgroups. The largest disparities were for cancers attributable to high consumption of sugar-sweetened beverages and low consumption of whole grains. Conclusions. Suboptimal diet contributes to substantial disparities in health and economic burdens of cancer among young adults, men, racial/ethnic minorities, and socioeconomically disadvantaged groups. (Am J Public Health. 2021;111(11):2008-2018. https://doi.org/10.2105/AJPH.2021.306475).