Evaluation of lifestyle, medical radiation exposure and epigenetic factors in relation to thyroid cancer in Koreans

Abstract

Introduction: The incidence of thyroid cancer has increased worldwide in recent decades, and the annual recorded percentage change of thyroid cancer was as high as 22.3% in Korea from 1999 to 2012. Although improved detection technologies and the relatively low cost of ultrasonography of the thyroid gland have been suggested as reasons for the increase in thyroid cancer in Korea, the possibility of a true increase has also been discussed. Particularly, except ionizing radiation exposure at early ages, environmental and genetic risk factors of thyroid cancer have not been established. The principle goal of the current study is to evaluate (1) alcohol consumption, (2) smoking, (3) obesity, (4) medical diagnostic radiation and (5) epigenetic profiles as risk factors of thyroid cancer in Korea. Methods: We used two data sources. First, the Thyroid Cancer Longitudinal Study (T-CALOS), which enrolled thyroid cancer patients at Seoul National University Hospital, Korea from 2010 to 2014, was used. Eligible subjects were those aged 20 years or older who agreed to participate, signed a written informed consent form, and completed a face-to-face interview to provide information regarding environmental and genetic factors and their general health condition. For thyroid cancer cases, we reviewed medical charts for clinical information, and this study included patients who were confirmed histologically by pathologists. For healthy controls, we conducted individual matching by age and sex from Health Examinees (HEXA), a community-based cohort study. For both cases and the controls, measured anthropometric information was collected, and obesity indicators including the body mass index (BMI), body surface area (BSA) and body fat percentage (BF%) were calculated. Secondly, data from the Korean Multi-center Cancer Cohort (KMCC) study, which collected epidemiologic information pertaining to general lifestyles, physical activity levels, and diet and reproductive factors in relation to the possible etiology of cancer, was used. The first enrollment of the KMCC was recorded in 1993, with follow-up investigations using a data link to the national cancer registry and the national death certificate system until December of 2013. For the statistical analyses, we used t-tests and Chi-square tests of the descriptive statistics. Regarding the associations between potential risk factors and thyroid cancer, odds ratios (ORs), hazard ratios (HRs) and their 95% confidence intervals (95%CIs) were calculated. We also evaluated the deoxyribonucleic acid (DNA) methylation levels of 96 selected gene sites in 90 blood DNA samples from both the subjects and the controls matched by age and sex from the hospital-based health examinees. Differences in the DNA methylation status between the two groups, the thyroid cancer cases and the controls, were compared. Results: In the T-CALOS study, while light or moderate drinking behavior was related to a reduced risk of differentiated thyroid cancer (DTC), acute heavy alcohol consumption (151 g or more per event or on a single occasion) was associated with increased risks in men (OR=2.2, 95%CI=1.3-3.9) and women (OR=3.6, 95%CI=1.5-8.6) compared with never-drinkers. Drinking alcohol beverages for 31 or more years was a significant risk factor for DTC for both men (31-40 years: OR=1.6, 95%CI=1.1-2.3

41+ years: OR=3.5, 95%CI=2.1-5.8) and women (31-40 years: OR=2.2, 95%CI=1.6-2.9

41+ years: OR=2.7, 95%CI=1.4-5.1) compared with never-drinkers. The consumption of a large amount of alcohol on a single occasion was also a significant risk factor, even after restricting DTC outcomes to tumor size, lymph node metastasis, extrathyroidal extension and TNM stage. For exposure to smoking, although active smoking itself was not associated with papillary thyroid cancer (PTC) risk, in subjects who had been exposed to early-age secondhand smoking at home during as they were growing up, smoking initiated before 20 years of age was associated with an increased level of PTC risk (OR=1.6, 95% CI=1.0-2.6) compared with never-smokers. Further, secondhand smoking among the never-smokers was also associated with increased PTC risk (men: OR=2.2, 95%CI=1.3-3.9

women: OR=1.5, 95%CI=1.3-1.7). Subjects with a high BMI (30kg/m2 or greater) at enrollment showed a significantly increased level of PTC risk in the men (OR=1.9, 95%CI=1.1-3.3) compared to those who were in the normal range of BMI (18.5-24.9kg/m2) among the men. The highest quartile of BSA at enrollment was also associated with PTC risk in both men and women (men: OR=2.2, 95%CI=1.5-3.1

women: OR=1.7, 95%CI=1.4-2.0) compared to those in the lowest quartile of BSA. Regarding obesity at 18-20 years of age, a higher BMI was associated with elevated PTC risk (BMI, 25.0-29.9: OR=4.0, 95%CI=3.2-5.0

BMI, 30.0+: OR=4.0, 95%CI=1.4-11.6) compared to the normal BMI range (18.5-24.9). A BMI of 25 or greater at age 18 was linked to a pronounced increase in PTC risk, particularly in men (men: OR=6.8, 95%CI=4.5-10.2

women: OR=3.2, 95%CI=2.4-4.2

p-heterogeneity=0.002). Regarding weight changes in middle-aged adults, subjects with a total weight gain of 10 kg or more after age 35 years were more likely to have PTC (men: OR=5.4, 95%CI=3.9–7.5

women: OR=3.4, 95%CI=2.9–3.9) compared with subjects with a stable weight (loss or gain <5 kg). A marked increase in BMI since age 35 (an annual average change of BMI ≥0.3 kg/m2/year) was related to elevated PTC risk, and the association was more pronounced for the larger PTC risk levels (<1 cm, OR, 2.3, 95%CI, 1.9–2.9

≥1 cm, OR, 4.0, 95%CI, 2.9-5.5, p-heterogeneity=0.005) compared to the low PTC risk levels. Based on data from the KMCC study, medical diagnostic radiation including X-ray radiography, upper gastrointestinal series (UGI), computerized tomography (CT), and mammography was not associated with increased thyroid cancer risk in general. Compared to those who remain unexposed to any of the five types of medical diagnostic radiation, those who were exposed to four combined sources (X-ray, UGI, CT, and mammography) showed a six-fold increase in their thyroid cancer risk level (HR=5.9, 95%CI=1.5–24.1). We observed distinct and unique patterns of methylation profiles for the two groups, i.e., the subjects and the controls. Conclusions: The factors of alcohol consumption, passive smoking, obesity at 18-20 years of age, and weight gain after age 35 was found to be potential risk factors of thyroid cancer risk in Koreans. Furthermore, the results of this study indicate that differences in DNA methylation levels can be used a biomarker for thyroid cancer.