(View plain language abstract)
The only established major risk factor for differentiated thyroid carcinomas (hereafter referred to, for brevity, as TC) is ionising radiation exposure. However, while radiation is unlikely to explain the upward thyroid cancer incidence trends observed over the last 30 years, the evidence for an association between TC risk and obesity has become stronger. Although little is known about the plausible biological explanations relating obesity and TC risk, results from in vivo and in vitro studies suggest that thyroid hormones may play an important role.
To explore these hypotheses, we investigated the associations of TC with body size within the large EPIC (European Prospective Investigation into Cancer and nutrition) study, using a cohort design, and measured concentrations of thyroid hormones (biomarkers related to thyroid function) in pre-diagnostic blood samples from the same cohort, using a nested case-control design. During follow-up, 508 incident cases of TC were identified in women from the EPIC cohort, and 58 in men. Among these, 357 (300 in women, 57 in men) provided blood at recruitment and were selected for the nested case-control study on thyroid hormones. Cox proportional hazard models were used to estimate hazard ratios.
Cohort study on body size and TC risk
In women, TC risk was significantly associated with body mass index (BMI), height, waist circumference and waist-to-hip ratio. The association with BMI was stronger in women below age 50. Corresponding associations for papillary TC were similar to those for all TC. In men, the only body size factors significantly associated with TC were height (although non-linear), and leg length.
Nested case-control study on thyroid hormones and TC risk
For each case of TC cancer case with biological samples, two controls in women and three controls in men (matched to the cases on several criteria) were identified within the EPIC cohort among subjects who provided blood and did not develop cancer at the time when the case developed cancer. Measurements of thyroid hormones, thyrotropin (TSH), thyroglobulin (Tg), and antibodies against thyroglobulin (from here on referred to as “thyroid hormones”) were undertaken. In both genders combined, TC risk was positively associated with Tg and negatively associated with TSH concentration. Areas under Receiver operating characteristic (ROC) curve were 56% and 74% for TSH and Tg level, respectively.
Our study lends further support to the presence of a moderate positive association between TC risk and overweight and obesity in women, but less so in men. In both genders, thyroglobulin and thyroid hormones concentrations were strongly associated with TC. However, neither marker has sufficient accuracy to be a screening test.
Thyroid cancer incidence has been rapidly increasing over the last two or three decades in high-resource countries, in which the disease is currently the second most frequent cancer, after breast cancer, in women below age 45. In high-resource countries, papillary and follicular carcinomas, known collectively as differentiated thyroid carcinoma (hereafter referred to, for brevity, as TC), account for approximately 75% and 13% of thyroid cancer, respectively. The only well-established risk factors for TC are exposure to ionizing radiation, especially during childhood, and history of benign thyroid disease. A moderate positive association between increased weight and height and TC risk has also been suggested. The biological explanations of the relationship between body size and thyroid cancer is not known but it may be related to variations in levels of hormones in different life periods.
In our project, we proposed to:
The EPIC project is a multi-centre prospective study that was set up to investigate relationships of cancer risk with nutrition and metabolic risk factors, which includes about half a million men and women, recruited through 23 research centres located in 10 western European countries. Baseline questionnaire data and anthropometric measurements from study participants were collected mostly in the period 1992 – 1998, as well as blood samples (from about 75% of the participants). Subjects were followed up to collect information on vital status and cancer diagnosis. During this follow-up time, 566 TC (508 in women, 58 in men) were identified. Out of these, we identified 357 cases (300 women and 57 men) with biological sample available, collected at recruitment, for analyses.
Associations between body size and TC risk were explored within the EPIC cohort using appropriate statistical analyses. Measurements of thyroid hormones, thyrotropin (TSH) thyroglobulin (TG) and antibodies against TG were performed on serum (plasma in certain instances) from the 357 cases with biological sample available, and on controls matched on the cases on several criteria. Appropriate statistical analyses were then conducted on this subset of the population to explore the association between differentiated thyroid cancer risk and blood concentrations of thyroid hormones (measured by commercially-available immunoassays), and to evaluate the potential use of biomarkers as screening tests.
In women, TC risk was significantly associated with body mass index, height, waist circumference, and waist-to-hip ratio. In men, the only body size factor significantly associated with TC was leg length. As far as the biomarker measurements are concerned, in both genders combined, TC risk was positively associated with Tg and negatively associated with TSH concentration. Neither marker, however, had sufficient accuracy to be a screening test.