Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Exposure to metal mixtures and telomere length in Bangladeshi children.

Telomere length is associated with chronic diseases and in younger populations, may represent a biomarker of disease susceptibility. As growing evidence suggests that environmental factors, including metals, may impact telomere length, we investigated the association between 17 metals measured in toenail samples and leukocyte relative telomere length (RTL), among 472 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. In single exposure linear regression models, a doubling of arsenic (As) and mercury (Hg) (µg/g) were associated with a -0.21 (95%CI: -0.032, -0.010; p=0.0005) and -0.017 (95%CI: -0.029, -0.004; p=0.006) difference in RTL, respectively. In Bayesian Kernel Machine Regression (BKMR) mixture models, the overall metal mixture was inversely associated with RTL (P-for-trend <0.001). Negative associations with RTL were observed with both log2-As and log2-Hg, while an inverted U-shaped association was observed for log2-zinc (Zn) with RTL. We found little evidence of interaction among metals. Sex-stratification identified stronger associations of the overall mixture and log2-As with RTL among females, compared to males. Our study suggests that As and Hg may independently influence RTL in mid-childhood. Further studies are needed to investigate potential long-term impacts of metal-associated telomere shortening in childhood on health outcomes in adult life.

Air quality and cancer risk in the All of Us Research Program.

INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.

Family history and gastric cancer incidence and mortality in Asia: a pooled analysis of more than half a million participants.

BACKGROUND: The family history of gastric cancer holds important implications for cancer surveillance and prevention, yet existing evidence predominantly comes from case-control studies. We aimed to investigate the association between family history of gastric cancer and gastric cancer risk overall and by various subtypes in Asians in a prospective study. METHODS: We included 12 prospective cohorts with 550,508 participants in the Asia Cohort Consortium. Cox proportional hazard regression was used to estimate study-specific adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between family history of gastric cancer and gastric cancer incidence and mortality, then pooled using random-effects meta-analyses. Stratified analyses were performed for the anatomical subsites and histological subtypes. RESULTS: During the mean follow-up of 15.6 years, 2258 incident gastric cancers and 5194 gastric cancer deaths occurred. The risk of incident gastric cancer was higher in individuals with a family history of gastric cancer (HR 1.44, 95% CI 1.32-1.58), similarly in males (1.44, 1.31-1.59) and females (1.45, 1.23-1.70). Family history of gastric cancer was associated with both cardia (HR 1.26, 95% CI 1.00-1.60) and non-cardia subsites (1.49, 1.35-1.65), and with intestinal- (1.48, 1.30-1.70) and diffuse-type (1.59, 1.35-1.87) gastric cancer incidence. Positive associations were also found for gastric cancer mortality (HR 1.30, 95% CI 1.19-1.41). CONCLUSIONS: In this largest prospective study to date on family history and gastric cancer, a familial background of gastric cancer increased the risk of gastric cancer in the Asian population. Targeted education, screening, and intervention in these high-risk groups may reduce the burden of gastric cancer.

Duration-sensitive association between air pollution exposure and changes in cardiometabolic biomarkers: Evidence from a predominantly African American cohort.

BACKGROUND: Ambient fine particulate matter (PM2.5) exposure has been related to cardiometabolic diseases, but the underlying biological pathways remain unclear at the population level. OBJECTIVE: To investigate the effect of PM2.5 exposure on changes in multiple cardiometabolic biomarkers across different exposure durations. METHOD: Data from a prospective cohort study were analyzed. Ten cardiometabolic biomarkers were measured, including ghrelin, resistin, leptin, C-peptide, creatine kinase myocardial band (CK-MB), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin, and interleukin-6 (IL-6). PM2.5 levels across exposure durations from 1 to 36 months were assessed. Mixed effect model was used to estimate changes in biomarker levels against 1 µg/m3 increase in PM2.5 level across different exposure durations. RESULTS: Totally, 641 participants were included. The average PM2.5 exposure level was 9 µg/m3. PM2.5 exposure was inversely associated with ghrelin, and positively associated with all other biomarkers. The magnitudes of these associations were duration-sensitive and exhibited a U-shaped or inverted-U-shaped trend. For example, the association of resistin were ß = 0.05 (95% CI: 0.00, 0.09) for 1-month duration, strengthened to ß = 0.27 (95% CI: 0.14, 0.41) for 13-month duration, and weakened to ß = 0.12 (95% CI: -0.03, 0.26) for 24-month duration. Similar patterns were observed for other biomarkers except for CK-MB, of which the association direction switched from negative to positive as the duration increased. Resistin, leptin, MCP-1, TNF-alpha, and troponin had a sensitive exposure duration of nearly 12 months. Ghrelin and C-peptide were more sensitive to longer-term exposure (>18 months), while NT-proBNP and IL-6 were more sensitive to shorter-term exposure (<6 months). CONCLUSION: PM2.5 exposure was associated with elevated levels in cardiometabolic biomarkers related to insulin resistance, inflammation, and heart injury. The magnitudes of these associations depended on the exposure duration. The most sensitive exposure durations of different biomarkers varied.

Returning personal genetic information on susceptibility to arsenic toxicity to research participants in Bangladesh.

BACKGROUND: There is growing consensus that researchers should offer to return genetic results to participants, but returning results in lower-resource countries has received little attention. In this study, we return results on genetic susceptibility to arsenic toxicity to participants in a Bangladeshi cohort exposed to arsenic through naturally-contaminated drinking water. We examine the impact on behavioral changes related to exposure reduction. METHODS: We enrolled participants from the Health Effects of Arsenic Longitudinal Study who had (1) high arsenic (≥150 µg/g creatinine) in a recent urine sample and (2) existing data on genetic variants impacting arsenic metabolism efficiency (AS3MT and FTCD). We used genetic data to recruit three study groups, each with n = 103: (1) efficient metabolizers (low-risk), (2) inefficient metabolizers (high-risk), and (3) a randomly-selected control group (NCT05072132). At baseline, all participants received information on the effects of arsenic and how to reduce exposure by switching to a low arsenic well. The two intervention groups also received their arsenic metabolism efficiency status (based on their genetic results). Changes in behavior and arsenic exposure were assessed using questionnaires and urine arsenic measures after six months. RESULTS: Clear decreases in urine arsenic after six months were observed for all three groups. The inefficient group self-reported higher levels of attempted switching to lower arsenic wells than the other groups; however, there was no detectable difference in urine arsenic reduction among the three groups. Participants showed strong interest in receiving genetic results and found them useful. The inefficient group experienced higher levels of anxiety than the other groups. Among the efficient group, that receiving genetic results did not appear to hinder behavioral change. CONCLUSION: Returning genetic results increased self-reported exposure-reducing behaviors but did not have a detectable impact on reducing urine arsenic over and above a one-on-one educational intervention.

Long-term exposure to ambient air pollution and measures of central hemodynamics and arterial stiffness among multiethnic Chicago residents.

OBJECTIVES: To examine whether long-term air pollution exposure is associated with central hemodynamic and brachial artery stiffness parameters. METHODS: We assessed central hemodynamic parameters including central blood pressure, cardiac parameters, systemic vascular compliance and resistance, and brachial artery stiffness measures [including brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR)] using waveform analysis of the arterial pressure signals obtained from a standard cuff sphygmomanometer (DynaPulse2000A, San Diego, CA). The long-term exposures to particles with an aerodynamic diameter < 2.5 µm (PM2.5) and nitrogen dioxide (NO2) for the 3-year periods prior to enrollment were estimated at residential addresses using fine-scale intra-urban spatiotemporal models. Linear mixed models adjusted for potential confounders were used to examine associations between air pollution exposures and health outcomes. RESULTS: The cross-sectional study included 2,387 Chicago residents (76% African Americans) enrolled in the ChicagO Multiethnic Prevention And Surveillance Study (COMPASS) during 2013-2018 with validated address information, PM2.5 or NO2, key covariates, and hemodynamics measurements. We observed long-term concentrations of PM2.5 and NO2 to be positively associated with central systolic, pulse pressure and BAR, and negatively associated with BAD, and BAC after adjusting for relevant covariates. A 1-µg/m3 increment in preceding 3-year exposures to PM2.5 was associated with 1.8 mmHg higher central systolic (95% CI: 0.98, 4.16), 1.0 mmHg higher central pulse pressure (95% CI: 0.42, 2.87), a 0.56%mmHg lower BAD (95% CI: -0.81, -0.30), and a 0.009 mL/mmHg lower BAC (95% CI: -0.01, -0.01). CONCLUSION: This population-based study provides evidence that long-term exposures to PM2.5 and NO2 is related to central BP and arterial stiffness parameters, especially among African Americans.

Association of Microsatellite Instability and Gene Expression Profile in Colorectal Carcinoma and Potential Implications for Therapy.

Background and Objective: In sporadic colorectal carcinomas (CRC), microsatellite instability (MSI) pathways play important roles. Previously, we showed differences in DNA methylation patterns in microsatellite stable (MSS) colorectal carcinomas and MSI-CRC. In the current study, we explore the similarities and differences in gene expression profiles in MSS and MSI at the gene level and at the pathway level to better understand CRC pathogenesis and/or the potential for therapeutic opportunities. Material and Methods: Seventy-one CRC patients (MSI = 18, MSS = 53) were studied. Paired tumor and adjacent normal tissues were used for genome-wide gene expression assays. Result: At the gene level, we compared the list of differentially expressed genes (fold change (FC) ≥ 3 and FDR < 0.05) in tumor tissues compared to corresponding normal tissue in CRC patients with MSI tumors (190 genes) and MSS tumors (129 genes). Of these, 107 genes overlapped. The list of genes that were differentially expressed in MSI tumors only showed enrichment predominantly in two broad categories of pathways-(a) Inflammation-related pathways including the interleukin-17 (IL-17) signaling pathway, tumor necrosis factor (TNF) signaling pathway, chemokine signaling, nuclear factor kappa B (NFκB) signaling, and cytokine-cytokine interactions, and (b) metabolism-related pathways, including retinol metabolism, steroid hormone biosynthesis, drug metabolism, pentose and glucoronate interconversions, and ascorbate and aldarate metabolism. The genes in inflammation-related pathways were up-regulated whereas genes in metabolism-related pathways were down-regulated in MSI tumor tissue. Pathway-level analysis also revealed similar results confirming the gene enrichment findings. For example, the 150 genes involved in the IL-17 signaling pathway were on average up-regulated by 1.19 fold (CI 1.16-1.21) in MSI compared to 1.14 fold (CI 1.13-1.16) in MSS patients (interaction p = 0.0009). Conclusions: We document an association between MSI status and differential gene expression that broadens our understanding of CRC pathogenesis. Furthermore, targeting one or more of these dysregulated pathways could provide the basis for improved therapies for MSI and MSS CRC.

The Impact of Neighborhood Disadvantage on Asthma Prevalence in a Predominantly African-American, Chicago-Based Cohort.

This study aimed to investigate the joint effect of neighborhood disadvantages on asthma prevalence and evaluate whether individual-level variables protect residents against neighborhood disadvantages. Data from the Chicago Multiethnic Prevention and Surveillance Study (from 2013-2020) were analyzed. Eight neighborhood characteristics were measured using the Chicago Health Atlas, including neighborhood unsafety, limited access to healthy food, neighborhood alienation, severe rent burden, vacant housing, single-parent household, neighborhood poverty, and unemployment. A structured questionnaire measured asthma diagnosis (childhood or adulthood) and individual-level variables including sex, age, income, education, and race. Weighted quantile sum (WQS) regression was used to evaluate the impact of neighborhood disadvantages. Stratified analysis was performed by income and education. A total of 6,592 participants (mean age = 53.5 (standard deviation, 11.1) years) were included. Most of the study population were non-Hispanic Black (82.5%) and reported an annual household income less than $15,000 (53%). Asthma prevalence was 23.6%. The WQS index, which represents the overall neighborhood disadvantages, was associated with asthma prevalence (odds ratio = 1.14, 95% confidence interval: 1.07, 1.22) when adjusted for individual-level confounders. Neighborhood poverty contributed 40.8% to the overall impact, followed by vacant housing (23.1%) and neighborhood alienation (22.9%). When stratified by individual-level income or education, no difference was observed for the association between WQS index and asthma prevalence.

A metabolome-wide case-control study of african american breast cancer patients.

BACKGROUND: Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae. METHODS: Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages. RESULTS: The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease. CONCLUSION: Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.

Association analysis identifies 65 new breast cancer risk loci.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Arsenic exposure from drinking water and endothelial dysfunction in Bangladeshi adolescents.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with ∼80% of CVD-related deaths occurring in low- and middle-income countries. Growing evidence suggests that chronic arsenic exposure may contribute to CVD through its effect on endothelial function in adults. However, few studies have examined the influence of arsenic exposure on cardiovascular health in children and adolescents. To examine arsenic's relation to preclinical markers of endothelial dysfunction, we enrolled 200 adolescent children (ages 15-19 years; median 17) of adult participants in the Health Effects of Arsenic Longitudinal Study (HEALS), in Araihazar, Bangladesh. Participants' arsenic exposure was determined by recall of lifetime well usage for drinking water. As part of HEALS, wells were color-coded to indicate arsenic level (<10 µg/L, 10-50 µg/L, >50 µg/L). Endothelial function was measured by recording fingertip arterial pulsatile volume change and reactive hyperemia index (RHI) score, an independent CVD risk factor, was calculated from these measurements. In linear regression models adjusted for participant's sex, age, education, maternal education, land ownership and body weight, individuals who reported always drinking water from wells with >50 µg/L arsenic had a 11.75% lower level of RHI (95% CI: -21.26, -1.09, p = 0.03), as compared to participants who drank exclusively from wells with ≤50 µg/L arsenic. Sex-stratified analyses suggest that these associations were stronger in female participants. As compared to individuals who drank exclusively from wells with ≤50 µg/L arsenic, the use of wells with >50 µg/L arsenic was associated with 14.36% lower RHI (95% CI: -25.69, -1.29, p = 0.03) in females, as compared to 5.35% lower RHI (95% CI: -22.28, 15.37, p = 0.58) in males for the same comparison. Our results suggest that chronic arsenic exposure may be related to endothelial dysfunction in adolescents, especially among females. Further work is needed to confirm these findings and examine whether these changes may increase risk of later adverse cardiovascular health events.

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.

Correction: A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

[This corrects the article DOI: 10.1371/journal.pgen.1007984.].

A Transcriptome and Methylome Study Comparing Tissues of Early and Late Onset Colorectal Carcinoma.

There is an increase in the incidence of early onset colorectal carcinoma (EOCRC). To better understand if there is any difference in molecular pathogenesis of EOCRC and late onset colorectal carcinoma (LOCRC), we compared the clinical, histological, transcriptome, and methylome profile of paired CRC and healthy colonic tissue from 67 EOCRC and 98 LOCRC patients. The frequency of stage 3 CRC, lymph node involvement, lymphovascular invasion, and perineural invasion was higher in the EOCRC group. Many of the cancer related pathways were differentially expressed in CRC tissue in both EOCRC and LOCRC patients. However, the magnitude of differential expression for some groups of genes, such as DNA damage repair genes and replication stress genes, were significantly less pronounced in the EOCRC group, suggesting less efficient DNA damage repair to be associated with EOCRC. A more marked methylation of "growth factor receptor" genes in LOCRC correlated with a more pronounced down-regulation of those genes in that group. From a therapeutic point of view, more over-expression of fatty acid synthase (FASN) among the LOCRC patients may suggest a better response of FASN targeted therapy in that group. The age of onset of CRC did not appear to modify the response of cis-platin or certain immune checkpoint inhibitors. We found some differences in the molecular pathogenesis in EOCRC and LOCRC that may have some biological and therapeutic significance.

Personal exposure to household air pollution and lung function in rural Bangladesh: A population-based cross-sectional study.

We assessed whether personal exposure to household air pollution [PM2.5 and black carbon (BC)] is associated with lung functions (FEV1, FVC, and their ratio) in non-smoking adults in rural Bangladesh. We measured personal exposure to PM2.5 using gravimetric analysis of PM2.5 mass and BC by reflectance measurement between April 2016 and June 2019. The average 24-hour PM2.5 and BC concentration was 141.0µgm-3 and 13.8µgm-3 for females, and 91.7 µgm-3 and 10.1 µgm-3 for males, respectively. A 1 µgm-3 increase in PM2.5 resulted in a 0.02 ml reduction in FEV1, 0.43 ml reduction in FVC, and 0.004% reduction in FEV1/FVC. We also found a similar inverse relationship between BC and lung functions (9.6 ml decrease in FEV1 and 18.5 ml decrease in FVC per 1µgm-3 increase in BC). A higher proportion of non-smoking biomass fuel users (50.1% of the females and 46.7% of the males) had restrictive patterns of lung function abnormalities, which need further exploration.