Age-Associated Mortality Risk in Papillary Thyroid Cancer: Does BRAF Make a Real Difference?

Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk

The dose of exposure to ionizing radiation appears to correlate with increased risk of thyroid microcarcinoma. Can ionizing radiation be a factor contributing to the increasing incidence of thyroid cancer around the world?

Background : Thyroid cancer is the most common endocrine cancer worldwide, with the incidence in women being three times that of men. Several reproductive and hormonal factors have been proposed as possible contributors to thyroid cancer risk, including age at menarche, parity, age at menopause, oral contraceptive use, surgical menopause, and hormone replacement therapy. Our study aimed to investigate potential reproductive/hormonal factors in a multiethnic population. Methods : A prospective cohort study of women of diverse racial and ethnic groups in the Multiethnic Cohort Study (n=118,344) was used. Included were 373 papillary thyroid cancer cases, linked to SEER cancer incidence and statewide death certificate files in Hawaii and California. Exposures investigated include age at menarche, parity, menopausal status and type, birth control use, and outcomes of first pregnancy. Cox proportional hazards models of papillary thyroid cancer were used to obtain relative risk (RR) and 95% confidence intervals (CI) to examine the associations with reproductive/hormonal factors. Results : We observed a statistically significant increased risk of papillary thyroid cancer for hysterectomy, oophorectomy, surgical menopause, and not having a child by age 20. The adjusted estimates for oophorectomy RR 1.66 (95% CI: 1.31, 2.11) and hysterectomy RR 1.82 (95% CI: 1.42, 2.34). Menopause due to surgery was associated with a 55% increase in risk (RR 1.55, 95% CI: 1.22, 1.97) and nulliparity vs ≤ 20 years of age at first livebirth was related to a 51% increased risk (adjusted RR 1.51, 95% CI: 1.07, 2.15). Adjustment factors included age and race/ethnicity and menopausal status, menopausal type, and oral contraception where appropriate. Former use of estrogen menopausal hormone therapy was associated with a 35% increased risk (adjusted RR: 1.35, 95% CI: 1.02, 1.79). No significant heterogeneity was seen in these associations by race/ethnicity (p het >0.48). Conclusion : The reproductive risk factors for papillary thyroid cancer reported in the literature were largely confirmed in our multiethnic population. Our analysis finds having a hysterectomy or oophorectomy and the use of MHT are associated with an increased risk of papillary thyroid cancer, and having a child at a younger age is associated with a reduction in thyroid cancer risk. Citation Format: Janine V. Abe, Song-Yi Park, Christopher A. Haiman, Loïc Le Marchand, Brenda Y. Hernandez, Lynne R. Wilkens. Reproductive factors and thyroid cancer risk: The multiethnic cohort study [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B125.

Previous studies on dietary iodine intake and the risk of papillary thyroid cancer (PTC) have demonstrated inconsistent results. We aimed to evaluate the association between urinary iodine concentration (UIC), a surrogate biomarker for dietary iodine intake, and the risk of thyroid cancer stratified by sex and age in an iodine-sufficient area. A hospital-based case–control study was conducted in Seoul, South Korea. A total of 492 cases of newly diagnosed PTC and 595 controls were included. Compared with the lowest quartile of creatine-adjusted UIC (< 159.3 μg/gCr), the highest quartile (≥ 1037.3 μg/gCr) showed an increased risk of PTC (odds ratio [OR] 1.49, 95% confidence interval [CI] 1.04–2.13), especially in those who were < 45 years old (ptrend = 0.01) compared with those who were ≥ 45 years old (ptrend = 0.48). For those who were < 45 years old, a positive association between creatinine-adjusted UIC and the risk of PTC was observed in both men (q4 vs. q1, OR 4.27, 95% CI 1.14–18.08) and women (OR 1.97, 95% CI 1.04–3.78). For those who were ≥ 45 years old, no association was found in any sex. Creatinine-adjusted UIC was positively associated with the risk of PTC, especially in those who were younger than 45 years for both men and women.

BackgroundSeveral studies have evaluated the association between obesity and thyroid cancer risk. However, the results remain uncertain. In this study, we conducted a meta-analysis to assess the association between obesity and thyroid cancer risk.Material/MethodsPublished literature from PubMed, EMBASE, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) were retrieved before 10 August 2014. We included all studies that reported adjusted risk ratios (RRs), hazard ratios (HRs) or odds ratios (ORs), and 95% confidence intervals (CIs) of thyroid cancer risk.ResultsThirty-two studies (n=12 620 676) were included in this meta-analysis. Obesity was associated with a significantly increased risk of thyroid cancer (adjusted RR=1.33; 95% CI, 1.24–1.42; I2=25%). In the subgroup analysis by study type, increased risk of thyroid cancer was found in cohort studies and case-control studies. In subgroup analysis by sex, both obese men and women were at significantly greater risk of thyroid cancer than non-obese subjects. When stratified by ethnicity, significantly elevated risk was observed in Caucasians and in Asians. In the age subgroup analysis, both young and old populations showed increased thyroid cancer risk. Subgroup analysis on smoking status showed that increased thyroid cancer risks were found in smokers and in non-smokers. In the histology subgroup analyses, increased risks of papillary thyroid cancer, follicular thyroid cancer, and anaplastic thyroid cancer were observed. However, obesity was associated with decreased risk of medullary thyroid cancer.ConclusionsOur results indicate that obesity is associated with an increased thyroid cancer risk, except medullary thyroid cancer.

Introduction: Worldwide, the increasing incidence of thyroid cancer, along with a parallel increase in obesity and metabolic disorders, suggests that modifications of lifestyle and environmental factors might explain the rise in thyroid cancer incidence (1). Objective: To investigate the association between metabolic syndrome and their elements and their possible association with the risk of thyroid cancer. Materials and Methods: We enrolled 200 patients, who underwent total thyroidectomy for multinodular goiter (Bethesda II-V categories on the basis of fine needle aspiration biopsy cytological examination). We included subjects with differentiated thyroid carcinoma, the ones with poorly differentiated, anaplastic, medullary thyroid carcinomas and secondary tumors were excluded from the analysis. Patients were divided into two groups, according to the post-surgical histological diagnosis: 60 patients diagnosed with papillary or follicular thyroid cancer and 60 diagnosed with benign thyroid disease. The patients had a mean age of 56.9 years old and the majority were females (90%). Relative risk of incident thyroid cancer was assessed by preoperative levels of body mass index (BMI), blood pressure, blood levels of glucose, cholesterol, triglycerides, and the presence of metabolic syndrome (according to the NCEP ATP III definition). The two groups had similar age, gender distribution, smoking habit. Mean BMI was slightly higher in the group with patients with differentiated thyroid cancer and the majority were obese (27.41 ± 5.38 kg/m2versus 26.42 ± 5.18 kg/m2). The patients from the differentiated thyroid cancer group showed a higher percentage of diabetes mellitus and impaired fasting glucose compared to the second group (20% versus 13%), with mean fasting blood sugar levels of 97 ± 2.69 mg/dl in the first group versus 73 ± 3.06 mg/dl in the second group. 30% of the patients from the differentiated thyroid cancer group presented criteria for metabolic syndrome. There was a positive correlation between the presence of hypertension and the diagnosis of differentiated thyroid cancer (p&amp;lt;0.05). Conclusion: Our study showed a potential association between metabolic risk factors and the diagnosis of differentiated thyroid cancer. Besides the improvement of diagnosis, thyroid cancer increasing incidence is probably due to environmental factors and lifestyle modifications. As a future perspective of this study and based on the hypothesis of glucose dependency of many tumor types, another therapeutic strategy can involve diet (low-carbohydrate, high-fat) in order to target metabolism in tumors and alter the Walburg phenothype. Reference: (1). Mele, C., Samà, M. et al. (2019). Circulating adipokines and metabolic setting in differentiated thyroid cancer, Endocrine Connections, 8(7), 997-1006.

Individual susceptibility to cancer is influenced by polymorphisms of genes encoding drug-metabolizing enzymes such as the glutathione S-transferases (GST). The null polymorphisms of the GSTM1 and GSTT1 genes have been associated to a modified risk of several cancers but studies of thyroid cancer have produced conflicting results. The aim of this study was to investigate the relationship between these polymorphisms and the risk of papillary thyroid cancer (PTC). A total of 188 patients with PTC and 247 controls were genotyped using a PCR-based assay. Odds ratios (OR) and 95% confidence intervals (CI) for each homozygous null genotype were determined. The frequency of each of the GSTM1 and GSTT1 null genotypes did not differ significantly between patients and controls (OR=0.83, 95%CI: 0.56-1.21; p=0.328; and OR=0.66, 95%CI: 0.39-1.12; p=0.123, respectively), but the frequency of individuals that had the combined GSTM1 null/GSTT1 null genotypes was significantly lower in the patient group (OR=0.50, 95%CI: 0.26-0.97; p=0.040). The GSTM1 null genotype was associated with a lower risk of advanced cancer stages (III/IV) (OR=0.50, 95%CI: 0.26-0.96; p=0.036) and the GSTT1 null genotype was associated with a lower risk of the follicular variant of PTC (OR=0.31, 95%CI: 0.10-0.97; p=0.044). These results suggest that GSTM1 and GSTT1 null genotypes are weak, yet possible, modifiers of the risk of PTC. This protective effect may be due to a role of the GSTM1 and GSTT1 encoded enzymes in the metabolic activation of putative thyroid carcinogens or in other pathways involved in thyroid carcinogenesis.

Dietary selenium intake and thyroid cancer risk in postmenopausal women

&lt;div&gt;Abstract&lt;p&gt;Given the female predominance of thyroid cancer, particularly in the reproductive age range, female sex hormones have been proposed as an etiology; however, previous epidemiological studies have shown conflicting results. We conducted a pooled analysis using individual data from nine prospective cohorts in the Asia Cohort Consortium to explore the association between 10 female reproductive and hormonal factors and thyroid cancer risk. Using Cox proportional hazards models, cohort-specific hazard ratios (HR) and 95% confidence intervals (CI) were estimated and then pooled using a random-effects model. Analyses were stratified by country, birth years, smoking status, and body mass index, and thyroid cancer risk based on age of diagnosis was also examined. Among 259,649 women followed up for a mean of 17.2 years, 1,353 incident thyroid cancer cases were identified, with 88% (&lt;i&gt;n&lt;/i&gt; = 1,140) being papillary thyroid cancer. Older age at first delivery (≥26 vs. 21–25 years) was associated with increased thyroid cancer risk (&lt;i&gt;P-&lt;/i&gt;trend = 0.003; HR = 1.16; 95% CI, 1.03–1.31), particularly when diagnosed later in life (≥55 vs. &lt; 55 years; &lt;i&gt;P&lt;/i&gt;-trend = 0.003; HR = 1.19; 95% CI, 1.02–1.39). Among younger birth cohorts, women with more number of deliveries showed an increased thyroid cancer risk [&lt;i&gt;P&lt;/i&gt;-trend = 0.0001, HR = 2.40; 95% CI, 1.12–5.18 (≥5 vs. 1–2 children)], and there was no substantial trend in older cohorts. Distinct patterns were observed for the number of deliveries and thyroid cancer risk across countries, with a significant positive association for Korea [&lt;i&gt;P&lt;/i&gt;-trend = 0.0008, HR = 1.89; 95% CI, 1.21–2.94 (≥5 vs. 1–2 children)] and nonsignificant inverse associations for China and Japan. Contextual and macrosocial changes in reproductive factors in Asian countries may influence thyroid cancer risk.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Prevention Relevance:&lt;/b&gt; This analysis of prospective cohort studies across three Asian countries highlights that older age at first birth is linked to increased thyroid cancer risk. As women delay motherhood, understanding these trends is vital for public health strategies addressing reproductive factors influencing thyroid cancer risk in these populations.&lt;/p&gt;&lt;/div&gt;

BackgroundThyroid nodules with indeterminate cytological features on fine needle aspiration biopsy specimens (FNABs) have a ~20% risk of thyroid cancer. BRAF V600E mutation and DNA methylation are useful markers to distinguish malignant thyroid neoplasm from benign. The aim of this study was to determine whether combined detection of BRAF V600E mutation and methylation markers on FNABs could improve the diagnostic accuracy of thyroid cancer.MethodsUsing pyrosequencing and quantitative methylation-specific PCR (Q-MSP) methods, FNABs from 79 and 38 patients with thyroid nodules in training and test groups, respectively, were analyzed for BRAF V600E mutation and gene methylation.ResultsBRAF V600E mutation was found in 30/42 (71.4%) and 14/20 (70%) FNABs in training and test groups, respectively. All BRAF V600E -positive samples were histologically diagnosed as papillary thyroid cancer (PTC) after thyroidectomy. As expected, BRAF mutation was not found in all benign nodules. Moreover, we demonstrated that the five genes, including CALCA, DAPK1, TIMP3, RAR-beta and RASSF1A, were aberrantly methylated in FNABs. Of them, methylation level of DAPK1 in PTCs was significantly higher than that in benign samples (P <0.0001). Conversely, methylation level of RASSF1A in PTCs was significantly lower than that in benign samples (P =0.003). Notably, compared with BRAF mutation testing alone, combined detection of BRAF mutation and methylation markers increased the diagnostic sensitivity and accuracy of PTC with excellent specificity.ConclusionOur data have demonstrated that combine analysis of BRAF mutation and DNA methylation markers on FNABs may be a useful strategy to facilitate the diagnosis of malignant thyroid neoplasm, particularly PTC.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6080878071149177.

RET germline pathogenic variants cause multiple endocrine neoplasia type 2 (MEN2), which is associated with medullary thyroid cancer. With increasing incidental identification of these variants in asymptomatic individuals outside family screening, these individuals' risk of medullary thyroid cancer and all-cause mortality without intervention remain unknown in this context. To evaluate the risk of medullary thyroid cancer and all-cause mortality in clinically unselected individuals with incidentally identified RET variants and assess whether the risk of medullary thyroid cancer differs from those with clinically ascertained RET variants. This prospective cohort study of 383 914 unrelated individuals from the clinically unselected UK population (UK Biobank, recruited in 2006-2010, with follow-up to June 2023) and 122 640 unrelated individuals from a US health system (Geisinger MyCode cohort, recruited 2004-2020, with follow-up to October 2023) compared medullary thyroid cancer risk in these cohorts with 1078 individuals who were clinically ascertained with suspicion of MEN2 from a UK routine practice. RET germline pathogenic variants causing MEN2. Frequency and the spectrum of pathogenic RET variants, risk of clinically present medullary thyroid cancer, and all-cause mortality without thyroidectomy were assessed using proportions with exact binomial 95% CIs and survival analysis adjusted for age at recruitment and sex. In the UK Biobank, 169 unrelated individuals (mean [SD] age at recruitment, 57.0 [8.1] years; 94 male [55.6%]) had a pathogenic RET variant (prevalence, 0.04% [95% CI, 0.04%-0.05%]). In the US health system-based cohort, 77 unrelated individuals (mean [SD] age at recruitment, 56.2 [17.8] years; 45 female [58.4%]) had a pathogenic RET variant (prevalence, 0.06% [95% CI, 0.05%-0.78%]). The variants were predominantly from the moderate-risk category per American Thyroid Association guidelines (168 individuals [99.4%] and 75 individuals [94.8%], respectively). The Kaplan-Meier estimated medullary thyroid cancer risk by age 75 years in variant carriers in the UK population was 2.2% (95% CI, 0.7%-6.9) and 19.3% (95% CI, 6.4%-30.2%) in US health system cohort. These risks were significantly lower compared with the clinically ascertained cohort with the matched variants (95.7% [95% CI, 82.1%-99.7%]). In the UK Biobank, most variant carriers (166 [98.2%]) did not undergo thyroidectomy, and their all-cause mortality by age 75 years was similar to noncarriers (6.1% [95% CI, 2.7%-13.8%] vs 5.7% [95% CI, 5.6%-5.8%]), with consistent findings in the US health system cohort. In this cohort study, moderate-risk RET variants were most common in incidental cases. The variants were associated with a substantially lower medullary thyroid cancer risk than clinically ascertained cases. This evidence addresses a current knowledge gap, enabling more informed clinical decision-making.

To investigate metabolic factors and their possible impact on risk of thyroid cancer. A prospective cohort study was conducted based on seven population-based cohorts in Norway, Austria, and Sweden, in the Metabolic syndrome and Cancer project (Me-Can). Altogether 578,700 men and women with a mean age of 44.0 years at baseline were followed for on average 12.0 years. Relative risk of incident thyroid cancer was assessed by levels of BMI, blood pressure, and blood levels of glucose, cholesterol, triglycerides, and by a combined metabolic syndrome (MetS) score. Risk estimates were investigated for quintiles, and a z score distribution of exposures was analyzed using Cox proportional hazards regression. During follow-up, 255 women and 133 men were diagnosed with thyroid cancer. In women, there was an inverse association between glucose and thyroid cancer risk, with adjusted RR: 95% CI was 0.61 (0.41-0.90), p trend = 0.02 in the fifth versus the first quintile, and a positive association between BMI and thyroid cancer risk with a significant trend over quintiles. There was no association between the other metabolic factors, single or combined (Met-S), and thyroid cancer. In women, BMI was positively, while blood glucose levels were inversely, associated with thyroid cancer.

GST profiling may be useful in the screening for thyroid nodule malignancy

The association between smoking, alcohol consumption, and thyroid cancer has been evaluated in observational studies, yet the results remain controversial. In the present investigation, we analyzed a longitudinal cohort study with representative data to determine the association between smoking, alcohol consumption, and thyroid cancer risk, allowing for risk modification due to age and sex. From the Korean National Health Insurance database, .subjects aged ≥20 who participated in health screening program in 2009 were identified and followed-up till 2017. The adjusted hazard ratio (aHR) for the risk of thyroid cancer was estimated by Cox proportional hazard model Results: During a mean follow-up period of 8.33 ± 0.57 years, out of 9,699,104 participants, 89,527 (0.9%) were diagnosed with thyroid cancer. In comparison with those who never smoked, current smokers [aHR: 0.74, 95% confidence interval (CI): 0.72-0.76)] had a decreased risk of thyroid cancer even though ex-smokers (aHR: 0.98, 95% CI: 0.96-1.01) did not. There was no dose-response relationship when the participants were examined with regard to the daily amount of smoking, duration of smoking, and pack-years. A decrease in the risk of thyroid cancer was observed according to both the number of drinking episodes per week and the number of glasses per once drinking (HR: 0.81, 95% CI: 0.74-0.88 for drinks consumed 7 times/week and HR: 0.87, 95% CI: 0.82-0.92 for ≥ 15 glasses once drinking vs. nondrinkers). A certain degree of alcohol consumption seemed to provoke a decreased risk of thyroid cancer as compared to those who did not drink (HR: 0.85, 95% CI: 0.81-0.89 for ≥ 40 g/week). The interaction of smoking and alcohol consumption was found to be significant (p-interaction < 0.0001), and sub-multiplicative. We found that the risk of thyroid cancer incidence was inversely associated with smoking and alcohol consumption. A sub-multiplicative interaction between smoking and alcohol intake on the risk of thyroid cancer was found. Further studies are needed to elucidate exactly how smoking and alcohol are related to the pathogenesis and the modification their effects may have on thyroid cancer development.

Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single-nucleotide polymorphisms (SNP). We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate ORs and 95% confidence intervals (CI) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P(trend). Nine of 10 top-ranking SNPs (P(trend) < 0.01) were located in the FTO (fat mass and obesity associated) gene region, whereas the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing. Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC. Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.