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Purpose Oral microbiome plays an important role in oral health and systemic diseases, including cancer. We aimed to prospectively investigate the association of oral microbiome with lung cancer risk. Methods We analyzed 156 incident lung cancer cases (73 European Americans and 83 African Americans) and 156 individually matched controls nested within the Southern Community Cohort Study. Oral microbiota were assessed using 16S rRNA gene sequencing in pre-diagnostic mouth rinse samples. Paired t test and the permutational multivariate analysis of variance test were used to evaluate lung cancer risk association with alpha diversity or beta diversity, respectively. Conditional logistic regression models were used to evaluate the association of individual bacterial abundance or prevalence with lung cancer risk. Results No significant differences were observed for alpha or beta diversity between lung cancer cases and controls. Abundance of families Lachnospiraceae_[XIV] , Peptostreptococcaceae_[XI] , and Erysipelotrichaceae and species Parvimonas micra was associated with decreased lung cancer risk, with odds ratios (ORs) and 95% confidence intervals (CIs) of 0.76 (0.59–0.98), 0.80 (0.66–0.97), 0.81 (0.67–0.99), and 0.83 (0.71–0.98), respectively (all p  < 0.05). Prevalence of five pre-defined oral pathogens were not significantly associated with overall lung cancer risk. Prevalence of genus Bacteroidetes_[G-5] and species Alloprevotella sp._oral_taxon_912 , Capnocytophaga sputigena , Lactococcus lactis , Peptoniphilaceae_[G-1] sp._oral_taxon_113 , Leptotrichia sp._oral_taxon_225 , and Fretibacterium fastidiosum was associated with decreased lung cancer risk, with ORs and 95% CIs of 0.55 (0.30–1.00), 0.36 (0.17–0.73), 0.53 (0.31–0.92), 0.43 (0.21–0.88), 0.43 (0.19–0.94), 0.57 (0.34–0.99), and 0.54 (0.31–0.94), respectively (all p  < 0.05). Species L. sp._oral_taxon_225 was significantly associated with decreased lung cancer risk in African Americans (OR [95% CIs] 0.28 [0.12–0.66]; p  = 0.00012). Conclusion Results from this study suggest that oral microbiota may play a role in the development of lung cancer.

Background Exome sequencing using next-generation sequencing technologies is a cost efficient approach to selectively sequencing coding regions of human genome for detection of disease variants. A significant amount of DNA fragments from the capture process fall outside target regions, and sequence data for positions outside target regions have been mostly ignored after alignment. Result We performed whole exome sequencing on 22 subjects using Agilent SureSelect capture reagent and 6 subjects using Illumina TrueSeq capture reagent. We also downloaded sequencing data for 6 subjects from the 1000 Genomes Project Pilot 3 study. Using these data, we examined the quality of SNPs detected outside target regions by computing consistency rate with genotypes obtained from SNP chips or the Hapmap database, transition-transversion (Ti/Tv) ratio, and percentage of SNPs inside dbSNP. For all three platforms, we obtained high-quality SNPs outside target regions, and some far from target regions. In our Agilent SureSelect data, we obtained 84,049 high-quality SNPs outside target regions compared to 65,231 SNPs inside target regions (a 129% increase). For our Illumina TrueSeq data, we obtained 222,171 high-quality SNPs outside target regions compared to 95,818 SNPs inside target regions (a 232% increase). For the data from the 1000 Genomes Project, we obtained 7,139 high-quality SNPs outside target regions compared to 1,548 SNPs inside target regions (a 461% increase). Conclusions These results demonstrate that a significant amount of high quality genotypes outside target regions can be obtained from exome sequencing data. These data should not be ignored in genetic epidemiology studies.

Introduction Cigarette smoking and alcohol drinking are well-known risk factors for various cancers. We aimed to determine a comprehensive profile of cancer risk associated with these lifestyle factors in predominantly low-income Americans. Methods We prospectively investigated the associations between cigarette smoking, alcohol drinking, and the risk of twelve cancer types among over 74 000 low-income Black and White adults from the Southern Community Cohort Study in the United States. We used the Cox proportional hazards models to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for these associations. Results Compared to never smokers, current smokers had an increased HR for cancers of lung (HR: 14.14, 95% CI: 11.47-17.42), liver and bile duct (HR: 3.19, 95% CI: 2.40-4.25), kidney (HR: 1.47, 95% CI: 1.10-1.96), pancreas (HR: 1.88, 95% CI: 1.41-2.50), oral and pharynx (HR: 3.83, 95% CI: 2.70-5.42), and bladder (HR: 2.81, 95% CI: 1.92-4.11), and a reduced risk of prostate cancer (HR: 0.78, 95% CI: 0.68-0.89) and uterine cancer (HR: 0.45, 95% CI: 0.32-0.63); former smokers also exhibited elevated risks for cancers of lung, liver and bile duct, kidney, and bladder; however, a decreased risk for the lung, liver and bile duct, and bladder cancers was observed with longer durations of smoking cessation, with HRs from 9.71, 2.26, and 2.28 for a duration of <10 years down to 4.28, 1.58, and 1.42 for a duration of 10-19 years, respectively. Compared to never-drinkers, participants who consumed more than 2 drinks per day had increased risks of liver and bile duct cancer (HR: 1.66, 95% CI: 1.29-2.13) and oral and pharynx cancer (HR: 2.15, 95% CI: 1.58-2.91). Conclusion Cigarette smoking and alcohol drinking were associated with an increased risk of multiple cancers. Our findings support efforts to control cigarette and alcohol consumption for cancer prevention in low-income U.S. populations.

The relationship between tissue-specific DNA methylation and cancer risk remains inadequately elucidated. Leveraging resources from the Genotype-Tissue Expression consortium, here we develop genetic models to predict DNA methylation at CpG sites across the genome for seven tissues and apply these models to genome-wide association study data of corresponding cancers, namely breast, colorectal, renal cell, lung, ovarian, prostate, and testicular germ cell cancers. At Bonferroni-corrected P  < 0.05, we identify 4248 CpGs that are significantly associated with cancer risk, of which 95.4% (4052) are specific to a particular cancer type. Notably, 92 CpGs within 55 putative novel loci retain significant associations with cancer risk after conditioning on proximal signals identified by genome-wide association studies. Integrative multi-omics analyses reveal 854 CpG-gene-cancer trios, suggesting that DNA methylation at 309 distinct CpGs might influence cancer risk through regulating the expression of 205 unique cis -genes. These findings substantially advance our understanding of the interplay between genetics, epigenetics, and gene expression in cancer etiology. The relationship between tissue-specific DNA methylation and cancer risk remains to be elucidated. Here, the authors predict DNA methylation at CpG sites for seven cancer types and investigate how these influence cancer risk.

Yoon Shin Cho, Mark Seielstad and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes in individuals of east Asian ancestry. They identify eight new loci associated with type 2 diabetes. We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3 , PEPD , FITM2-R3HDML-HNF4A , KCNK16 , MAEA , GCC1-PAX4 , PSMD6 and ZFAND3 . GLIS3 , which is involved in pancreatic beta cell development and insulin gene expression 1 , 2 , is known for its association with fasting glucose levels 3 , 4 . The evidence of an association with T2D for PEPD 5 and HNF4A 6 , 7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE 2 ) with overall and cause-specific mortality and examine potential effect modifiers, we obtained urinary PGE-M levels of 2927 non-cancerous adults from our previous case-control studies nested in the Shanghai Women’s Health Study and Shanghai Men’s Health Study, two cohort studies conducted in Shanghai, China. Mortality data and modifiable factors associated with urinary PGE-M were obtained from the parent cohort studies. Using linear regression models, we found that high urinary PGE-M levels were significantly associated with low education, heaving smoking, old age at urine collection, and abdominal obesity. Using Cox proportional hazards models, we found that increase (per standard deviation) of urinary PGE-M levels were significantly associated with overall mortality (adjusted hazard ratio = 1.19, 95% confidence interval: 1.07, 1.33) and particularly deaths from cardiometabolic diseases (adjusted hazard ratio = 1.27, 95% confidence interval: 1.11, 1.44). The increased death risks persisted across different time intervals during the follow-up and were stronger among participants who were younger than 60 ( P  = 0.0014 for all- cause mortality and P  = 0.007 for deaths from cardiometabolic diseases) at urine collection or perhaps among those who had higher education.

BackgroundAfrican 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.MethodsWe 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.ResultsNo 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).ConclusionsPreviously reported associations between oral taxa and pancreatic cancer were not present in this African-American population overall.

Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs) could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ) and low metastatic (MOLF/EiJ) mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL) SNPs with disease-free survival, consistent with the mouse studies.

Background Residing in a disadvantaged neighborhood has been linked to increased mortality. However, the impact of residential segregation and social vulnerability on cause-specific mortality is understudied. Additionally, the circulating metabolic correlates of neighborhood sociodemographic environment remain unexplored. Therefore, we examined multiple neighborhood sociodemographic metrics, i.e., neighborhood deprivation index (NDI), residential segregation index (RSI), and social vulnerability index (SVI), with all-cause and cardiovascular disease (CVD) and cancer-specific mortality and circulating metabolites in the Southern Community Cohort Study (SCCS). Methods The SCCS is a prospective cohort of primarily low-income adults aged 40–79, enrolled from the southeastern United States during 2002–2009. This analysis included self-reported Black/African American or non-Hispanic White participants and excluded those who died or were lost to follow-up ≤ 1 year. Untargeted metabolite profiling was performed using baseline plasma samples in a subset of SCCS participants. Results Among 79,631 participants, 23,356 deaths (7214 from CVD and 5394 from cancer) were documented over a median 15-year follow-up. Higher NDI, RSI, and SVI were associated with increased all-cause, CVD, and cancer mortality, independent of standard clinical and sociodemographic risk factors and consistent between racial groups (standardized HRs among all participants were 1.07 to 1.20 in age/sex/race-adjusted model and 1.04 to 1.08 after comprehensive adjustment; all P  < 0.05/3 except for cancer mortality after comprehensive adjustment). The standard risk factors explained < 40% of the variations in NDI/RSI/SVI and mediated < 70% of their associations with mortality. Among 1110 circulating metabolites measured in 1688 participants, 134 and 27 metabolites were associated with NDI and RSI (all FDR < 0.05) and mediated 61.7% and 21.2% of the NDI/RSI-mortality association, respectively. Adding those metabolites to standard risk factors increased the mediation proportion from 38.4 to 87.9% and 25.8 to 42.6% for the NDI/RSI-mortality association, respectively. Conclusions Among low-income Black/African American adults and non-Hispanic White adults living in the southeastern United States, a disadvantaged neighborhood sociodemographic environment was associated with increased all-cause and CVD and cancer-specific mortality beyond standard risk factors. Circulating metabolites may unveil biological pathways underlying the health effect of neighborhood sociodemographic environment. More public health efforts should be devoted to reducing neighborhood environment-related health disparities, especially for low-income individuals.

Background Molecular classification of breast cancer is an important prognostic factor. The distribution of molecular subtypes of breast cancer and their prognostic value has not been well documented in Asians. Methods A total of 2,791 breast cancer patients recruited for a population-based cohort study were evaluated for molecular subtypes of breast cancer by immunohistochemical assays. Data on clinicopathological characteristics were confirmed by centralized pathology review. The average follow-up of the patients was 53.4 months. Overall and disease-free survival by molecular subtypes of breast cancer were evaluated. Results The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and triple-negative subtypes were 48.6%, 16.7%, 13.7%, and 12.9%, respectively. The luminal A subtype was more likely to be diagnosed in older women (P = 0.03) and had a stronger correlation with favorable clinicopathological factors (smaller tumor size, lower histologic grade, and earlier TNM stage) than the triple-negative or HER2 subtypes. Women with triple-negative breast cancer had a higher frequency of family history of breast cancer than women with other subtypes (P = 0.048). The 5-year overall/disease-free survival percentages for the luminal A, luminal B, HER2, and triple-negative subtypes were 92.9%/88.6%, 88.6%/85.1%, 83.2%/79.1%, and 80.7%/76.0%, respectively. A similar pattern was observed in multivariate analyses. Immunotherapy was associated with improved overall and disease-free survival for luminal A breast cancer, but reduced disease-free survival (HR = 2.21, 95% CI, 1.09-4.48) for the HER2 subtype of breast cancer. Conclusions The triple-negative and HER2 subtypes were associated with poorer outcomes compared with the luminal A subtype among these Chinese women. The HER2 subtype was more prevalent in this Chinese population compared with Western populations, suggesting the importance of standardized HER2 detection and anti-HER2 therapy to potentially benefit a high proportion of breast cancer patients in China.