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Biomarkers can provide distinct information about cancer risk factors in populations from diverse ancestries and with different exposure patterns by measuring the internal dose of carcinogens. While similar environmental exposures can lead to different cancer risks across racial or ethnic groups, seemingly different exposures can cause the same cancers because they produce the same biomarkers in the body. Smoke-related biomarkers are among the most commonly studied biomarkers in relation to cancer, and they include tobacco-specific biomarkers (nicotine metabolites and tobacco-specific nitrosamines) and biomarkers which can result from exposure to tobacco and non-tobacco pollutants (polycyclic aromatic hydrocarbon and volatile organic compounds). Biomonitoring is superior to self-reported exposure assessment because it is less prone to information and recall biases. However, biomarkers generally reflect recent exposure determined by their metabolism and half-life and how they are stored in and excreted from the body. Many biomarkers are correlated because the sources of exposure usually contain several carcinogens at the same time, making it difficult to identify specific chemicals which lead to cancer. Despite these challenges, biomarkers will continue to be essential to cancer research. Prospective studies, with detailed exposure assessment and large sample sizes from diverse backgrounds, along with studies designed to enrich the methodology of biomarker research are the necessary steps in that direction.See related article by Cigan et al., p. 306

A male predominance was observed in esophageal and gastric cancers, though present limited data has revealed variations by age. We aim to investigate the global age-specific sex differences in esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). Data on esophageal and gastric cancers incidence by diagnosis year, sex, histology, subsite and age group were extracted from 171 registries in 54 countries included in the last two volumes (X and XI, 2003-2012) of Cancer Incidence in Five Continents, which contributing to over 80% of the global burdens of these cancers. Age-standardized incidence rates (ASIRs) and male-to-female ASIRs ratios were estimated for esophageal and gastric cancers, by histological subtype and subsite, globally and by country. We consistently observed a male predominance in esophageal and gastric cancers across the world from 2003 to 2012, with male-to-female ASIRs ratios of 6.7:1 for EAC, 3.3:1 for ESCC, 4.0:1 for GCC and 2.1:1 for GNCC. The sex differences were consistent across time periods but varied significantly by age across the life span. Across the four cancer types, the male-to-female incidence rate ratios increased from young ages, approaching a peak at ages 60-64, but sharply declined thereafter. Similar "low-high-low" trends of age-specific sex ratio were observed in other digestive cancers including liver, pancreas, colon and rectum with peak ages ranging from 50 to 65. Age-dependent risk factors warrant further investigation to aid our understanding of the underlying etiologies of esophageal and gastric cancers by histological subtype and subsite.

Introduction: There is a critical need for complex microbiome quality control standards representing population-based samples for microbial community profiling and analysis in large scale epidemiologic studies. Methods: We developed standard quality control samples from five volunteers with different phenotypes, comprising one obese female, one healthy male, one male on a low-carb diet, one infant, and one male with Crohn’s Disease, and evaluated their microbial metagenomic profiles within three laboratories at two different timepoints. To quantify the percentage of microbiome variability explained by donors, laboratory and sequencing run, a distance-based coefficient of determination R2 was estimated using a permutational multivariate analysis of variance. In addition, we calculated the intraclass correlation coefficients (ICC) for the relative abundance of the most abundant species, two alpha diversity metrics (i.e., observed number of species and Shannon index) and the first principal coordinates of three beta diversity matrices (i.e., Bray-Curtis, Jaccard and Aitchison) to estimate the accuracy of fecal microbial profiles between the three different laboratories as well as within the laboratories. Results: The variability introduced by the phenotype of the donors explained 82.7% to 95.3% of the overall variability, which was higher than the variability introduced by the laboratories (1.8% to 3.1%) and the sequencing runs (0.6% to 1.7%) - the residual percent variance explained varied between 2.2% and 12.4%. Observations based on principal coordinates analysis showed that samples clustered by donor and not by laboratory or sequencing runs. The five donor clusters were well separated and very distinct. Based on the comparison of species relative abundances, each donor displayed very different microbial profiles; and the microbial profiles of each donor were comparable between the three different laboratories and the two sequencing runs in each laboratory. The reproducibility within and between the laboratories was good to excellent for most diversity metrics (ICCs higher than 0.97) and species relative abundances (range, ICCs=0.70-0.99); however, the reproducibility of the observed number of species was moderate (ICC=0.64 for the first laboratory, ICC=0.78 for the second laboratory, ICC=0.81 for the third laboratory, and ICC=0.42 between the laboratories). Conclusions: These standard quality control samples can be used as a reference in future population-based epidemiologic studies to pool or meta-analyze microbiome data. Citation Format: Semi Zouiouich, Smriti Karwa, Yunhu Wan, Andrew Chan, Joseph Petrosino, Emma Allen-Vercoe, Rob Knight, Jianxin Shi, Mitchell Gail, Christian Abnet, Emily Vogtmann, Rashmi Sinha. Quality control samples for future population-based microbiome studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3050.

The etiology of esophageal squamous cell carcinoma (ESCC) in the high risk area of northern Iran is only partially known. We aimed to investigate prolonged animal contact as a risk factor for ESCC in this population. From 2003 to 2007, we administered a validated questionnaire to 300 ESCC cases and 571 randomly selected controls matched for neighborhood of residence, age (±2 years) and sex. Questions on lifelong exposure to equines, ruminants, canines, and poultry, including duration and level of contact, were asked in a face-to-face interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. A total of 94.7% of cases and 68.7% of controls reported lifelong history of contact with ruminants. After controlling for potential confounders, contact with ruminants was associated with an eightfold increase (95% CI: 3.92-14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner. Contact with equines and poultry did not significantly change associated OR for ESCC risk and contact with ruminants. OR (95% CI) for contact with canines was 1.99 (1.35-2.93) which after exclusion of contact with ruminants was not significant (OR for contact only with canine: 3.18, 95% CI: 0.73-13.17). These results add to the evidence that contact with ruminants may increase the risk of ESCC. © 2014 UICC.

Esophageal squamous cell carcinoma (ESCC) is a major health problem in many developing countries including Iran. ESCC has a very poor prognosis, largely due to late diagnosis. As a first step in developing an early detection and treatment program, we conducted a population-based endoscopic screening for ESCC and its precursor lesion, esophageal squamous dysplasia (ESD) in asymptomatic adults from Golestan Province, northern Iran, a high-risk area for ESCC, to evaluate the feasibility of such a program and to document the prevalence and risk factor correlates of ESD.This cross-sectional study was conducted among participants of the Golestan Cohort Study (GCS), a population-based cohort of 50,000 adults in eastern Golestan Province. Randomly selected GCS participants were invited by telephone. Those who accepted were referred to a central endoscopy clinic. Eligible subjects were consented and then asked to fill in a brief questionnaire. Detailed information about selected risk factors was obtained from the GCS main database. Endoscopic examination with Lugol's iodine staining was performed, biopsies were taken from unstained lesions as well as the normally stained mucosa of the esophagus, and the biopsies were diagnosed by expert pathologists according to previously described criteria.In total, 1906 GCS subjects were invited, of whom only 302 subjects (15.8%) were successfully enrolled. Esophagitis (29.5%) and ESD (6.0%) were the most common pathological diagnoses. Turkmen ethnicity (adjusted OR = 8.61; 95%CI: 2.48-29.83), being older than the median age (OR = 7.7; 95% CI: 1.99-29.87), and using deep frying cooking methods (OR = 4.65; 95%CI: 1.19-18.22) were the strongest predictors for ESD. There were significant relationships between esophagitis and smoking (p-value0.001), drinking hot tea (P value = 0.02) and lack of education (P value = 0.004).We observed a low rate for participation in endoscopic screening. Overall prevalence of ESD was 6.0%. Developing non-endoscopic primary screening methods and screening individuals with one or more risk factors may improve these rates.

Background: The northeastern region of Iran has some of the highest rates of esophageal squamous cell carcinoma (ESCC) in the world. Materials and Methods: To investigate the role of polycyclic aromatic hydrocarbons (PAHs) in the etiology of ESCC in northeastern Iran, we measured urine 1-hydroxypyrene glucuronide (1-OHPG), a stable PAH metabolite, in 99 inhabitants of this area. Results: The median urine 1-OHPG in participants of this study was 4.2 pmol/ml. Forty-two subjects (42%) had levels ranging from 1 to 5 pmol/ml, indicative of moderate PAH exposure, and 41 (41%) had levels above 5 pmol/ml, indicative of very high exposure. Further analysis showed that 1-OHPG levels were high in all subgroups of our study subjects, including both sexes, rural and urban dwellers, and smokers and non-smokers. Only 15% of the variance in 1-OHPG was explained by age, sex, residence, smoking, nass, or opium consumption. This pattern of PAH exposure parallels the ESCC incidence pattern seen in this area. Conclusion: We conclude that people in northeastern Iran are exposed to widespread and very high levels of PAH, largely from unknown sources, and this may contribute to the high rates of ESCC observed in this area.

Purpose: To investigate the risk factors for squamous-cell carcinoma of the conjunctiva (SCCC) and other eye cancers in the NIH-AARP Diet and Health Study. Methods: We estimated incidence rates and associations with age, sex, race/ethnicity and ultraviolet radiation using Cox proportional hazards models. Results: The incidence was 37.3 per 106 for all eye cancers (N = 178), 8.4 per 106 for SCCC (N = 40) and 28.9 per 106 for other eye cancers (N = 138). For all eye cancers, the incidence was lower in women than in men (hazard ratio [HR] = 0.38, 95% CI: 0.26, 0.55) and in persons aged ≤60 years than those aged >60 years (HR = 0.51, 95% CI: 0.36, 0.72). The incidence was higher, but not statistically significant, in those with an average net erythemal exposure >170 versus ≤170 (HR = 1.19, 95% CI: 0.88, 1.63) and lower in those residing at latitudes >35° versus ≤35° (HR = 0.81, 95% CI: 0.61, 1.09). The patterns were similar for SCCC in sex, age, race/ethnicity and average net erythemal exposure, but not statistically significant. Conclusion: The incidence of all eye cancers was associated with male sex and older age. The same patterns were observed for SCCC. The associations reported here might be surrogates of exposure to ultraviolet radiation, although more follow-up is needed to obtain precise results.

Most studies that have evaluated the association between combined lifestyle factors and mortality outcomes have been conducted in populations of developed countries.The aim of this study was to examine the association between combined lifestyle scores and risk of all-cause and cause-specific mortality for the first time among Iranian adults.The study population included 50,045 Iranians, 40 - 75 years of age, who were enrolled in the Golestan Cohort Study, between 2004 and 2008. The lifestyle risk factors used in this study included cigarette smoking, physical inactivity, and Alternative Healthy Eating Index. The lifestyle score ranged from zero (non-healthy) to 3 (most healthy) points. From the study baseline up to analysis, a total of 4691 mortality cases were recorded. Participants with chronic diseases at baseline, outlier reports of calorie intake, missing data, and body mass index of less than 18.5 were excluded from the analyses. Cox regression models were fitted to establish the association between combined lifestyle scores and mortality outcomes.After implementing the exclusion criteria, data from 40,708 participants were included in analyses. During 8.08 years of follow-up, 3,039 cases of all-cause mortality were recorded. The adjusted hazard ratio of a healthy lifestyle score, compared with non-healthy lifestyle score, was 0.68 (95% CI: 0.54, 0.86) for all-cause mortality, 0.53 (95% CI: 0.37, 0.77) for cardiovascular mortality, and 0.82 (95% CI: 0.53, 1.26) for mortality due to cancer. When we excluded the first two years of follow up from the analysis, the protective association between healthy lifestyle score and cardiovascular death did not change much 0.55 (95% CI: 0.36, 0.84), but the inverse association with all-cause mortality became weaker 0.72 (95% CI: 0.55, 0.94), and the association with cancer mortality was non-significant 0.92 (95% CI: 0.58, 1.48). In the gender-stratified analysis, we found an inverse strong association between adherence to healthy lifestyle and mortality from all causes and cardiovascular disease in either gender, but no significant relationship was seen with mortality from cancer in men or women. Stratified analysis of BMI status revealed an inverse significant association between adherence to healthy lifestyle and mortality from all causes, cardiovascular disease and cancer among non-obese participants.We found evidence indicating that adherence to a healthy lifestyle, compared to non-healthy lifestyle, was associated with decreased risk of all-cause mortality and mortality from cardiovascular diseases in Iranian adults.

Opium use has been associated with higher risk of cancers of the esophagus, bladder, larynx, and lung; however, no previous study has examined its association with gastric cancer. There is also little information on the associations between hookah (water pipe) smoking or the chewing of tobacco products and the risk of gastric cancer. In a case-control study in Golestan Province of Iran, we enrolled 309 cases of gastric adenocarcinoma (118 noncardia, 161 cardia and 30 mixed-location adenocarcinomas) and 613 matched controls. Detailed information on long-term use of opium, tobacco products and other covariates were collected using structured and validated lifestyle and food frequency questionnaires. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were obtained using conditional logistic regression models. Opium use was associated with an increased risk of gastric adenocarcinoma, with an adjusted OR (95% CI) of 3.1 (1.9-5.1), and this increased risk was apparent for both anatomic subsites (cardia and noncardia). There was a dose-response effect, and individuals with the highest cumulative opium use had the strongest association (OR: 4.5; 95% CI: 2.3-8.5). We did not find a statistically significant association between the use of any of the tobacco products and risk of gastric adenocarcinoma, overall or by anatomic subsite. We showed, for the first time, an association between opium use and gastric adenocarcinoma. Given that opium use is a traditional practice in many parts of the world, these results are of public health significance. Copyright © 2013 UICC.