Abstract
Objective
Previous reports suggest that a high body mass index (BMI) increases the risk of thyroid carcinoma. However, it remains unclear whether a high BMI is associated with the risk of the BRAFV600E mutation. We aimed to assess whether a high BMI is associated with an increased risk of the BRAFV600E mutation.
Design and Methods
We screened 6558 PTC patients who had undergone BRAFV600E mutation testing between January 2009 and December 2017. After exclusion, 6438 PTC patients were enrolled. We used logistic regression, and restricted cubic spline plots of the adjusted odds ratios (ORs) were illustrated to model the relationship between BMI and the BRAFV600E mutation.
Results
Of the 6438 patients, 5102 (79.2%) had the BRAFV600E mutation, and 4954 (76.9%) were female. The median BMI was 23.8 (21.6–26.2) kg/m2. The primary tumor size was ≤1 cm in 4226 patients (65.6%) and >1 cm in 2212 patients (34.4%). The BRAFV600E mutation was significantly associated with high BMI only in patients with a primary tumor size >1 cm (OR: 1.034; 95% CI: 1.003–1.065; P = 0.029), whereas no clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; 95% CI: 0.984–1.030; P = 0.570). Gender was not a significant factor in either group.
Conclusions
Our study found that a higher BMI was positively associated with the BRAFV600E mutation in patients with a primary tumor size >1 cm. These results suggest that the association between BMI and the BRAFV600E mutation status differs depending on primary tumor size.
Significance Statement
Obesity has been suggested as a potential risk factor for thyroid carcinoma. The aim of this study was to assess the association between BMI and the BRAFV600E mutation. In this study, the BRAFV600E mutation was significantly associated with a high BMI only in a primary tumor size >1 cm (OR: 1.034; P = 0.029). No clear association was found in patients with a primary tumor size ≤1 cm (OR: 1.007; P = 0.570). The association between BMI and the BRAFV600E mutation status differs depending on the primary tumor size.
Introduction
The incidence of thyroid carcinoma has rapidly increased in many countries over the past few decades (1, 2, 3), but there have been no substantial changes in the mortality rate (4, 5). The use of more sensitive diagnostic techniques, such as ultrasonography, computed tomography, and magnetic resonance imaging, combined with increased medical surveillance, is thought to be primarily responsible for over-diagnosis (6). However, the incidence has been increasing in all tumor sizes (7). Thus, over-diagnosis and early detection cannot fully explain the increasing incidence of thyroid carcinoma, and there may have been a true increase in disease incidence (6). In previous reports, obesity has been suggested as a potential cause of the increasing incidence of thyroid carcinoma. Although the relationship between obesity and thyroid carcinoma is controversial, most studies suggest that obesity is positively associated with thyroid carcinoma risk in both men and women (8, 9, 10, 11).
Recently, Rahman et al. demonstrated a positive association between body mass index (BMI) and B-type Raf kinase (BRAFV600E) mutation in both men and women based on a large population-based study in Australia (12). de Biase et al. reported that the BRAFV600E mutation occurs in the early stages of cancer progression preceding histological changes (13) and may function as an initial transforming event during thyroid carcinoma development (14). Based on previous reports, obesity is a potential risk factor for thyroid carcinoma through mechanisms such as DNA damage from oxidative stress (15), and it has a positive association with higher BMI. Therefore, obesity might be a risk factor for the BRAFV600E mutation. Additionally, the prevalence of the BRAFV600E mutation in papillary thyroid carcinoma (PTC) ranges from 30% to greater than 80% (16, 17), varying by geographic region and dietary components such as iodine intake (18). Thus, we conducted this study to investigate the association between BMI and the BRAFV600E mutation in a large East-Asian cohort of a tertiary referral center in Korea.
Materials and methods
Study population and clinicopathological assessments
We screened the 6558 patients with PTC confirmed by pathology who underwent BRAFV600E mutation testing at the Samsung Medical Center from January 2009 to December 2017. Of them, we excluded 120 patients due to incomplete data or due to being younger than 18 years old.
Anthropometric factors, such as height and weight, were measured on the first day of thyroid surgery. The body mass index (BMI) was defined as weight in kilograms divided by the square of height in meters (kg/m2). Age at diagnosis, gender, BRAFV600E mutational status, final pathology reports, alcohol consumption status, and smoking status were obtained from the electronic medical record system. The primary tumor size was determined as the maximum tumor diameter in centimeters on the pathological report. Alcohol consumption status and smoking status were assessed using a structured questionnaire on the first day of thyroid surgery.
We categorized patients into two groups based on primary tumor size: ≤1 cm (T1a) and >1 cm. This study was approved by the Institutional Review Board of Samsung Medical Center (IRB no. 2023-02-132), and informed consent was waived by the committee due to the retrospective nature of the study.
Detection of the BRAFV600E mutation
We performed a dual-priming oligonucleotide (DPO)-based multiplex polymerase chain reaction (PCR) to identify the BRAFV600E mutation. Detailed methods were described in a previous report (19).
Statistical analysis
Continuous variables were presented as median with interquartile range (IQR), and categorical variables were presented as number and frequency. The Kruskal–Wallis test was used to compare continuous variables, while the chi-square test or Fisher’s exact test was used to compare categorical variables. A logistic regression model was used to identify risk factors for BRAFV600E mutation, and odds ratios (ORs) and 95% CIs were presented. Multivariable regression was performed using backward elimination, and we set the P-value to enter the model at P < 0.10. A P-value less than 0.05 was considered statistically significant. Restricted cubic spline plots of the adjusted ORs were illustrated to model the relationship between BMI and the BRAFV600E mutation. The association between BMI and the BRAFV600E mutation was adjusted for age, alcohol consumption status, and smoking status. Statistical analysis was executed using SPSS version 25.0 for Windows (IBM), SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and R 3.6.1 (Vienna, Austria; http://www.R-project.org/).
Results
Baseline characteristics
The clinicopathological characteristics of the 6438 patients are presented in Table 1. Among them, the median age was 47 years (39–55 years), and 4954 (76.9%) were female. The median (IQR) height and weight were 160.3 (155.6–166.1) cm and 60.8 (54.4–69.4) kg, respectively. The median BMI was 23.8 (21.6–26.2) kg/m2. Of the enrolled patients, 336 (5.2%) were current smokers, and 1464 (22.7%) were current drinkers. BRAFV600E mutation was detected in 5102 (79.2%) patients.
Clinicopathological characteristics of the 6438 enrolled patients.
Characteristics | Values |
---|---|
Age, years (median, IQR) | 47 (39–55) |
Gender (n, %) | |
Female | 4954 (76.9) |
Male | 1484 (23.1) |
Height, cm (median, IQR) | 160.3 (155.6–166.1) |
Weight, kg (median, IQR) | 60.8 (54.4–69.4) |
BMI, kg/m2 (median, IQR) | 23.8 (21.6–26.2) |
Primary tumor size, cm (median, IQR) | 0.8 (0.6–1.2) |
Primary tumor size, cm (n, %) | |
≤1 cm | 4226 (65.6) |
1 cm | 2212 (34.4) |
N stage | |
N0/Nx | 3732 (58.0) |
N1a | 1984 (30.8) |
N1b | 722 (11.2) |
Smoking status (n, %) | |
Never smoker | 5644 (87.7) |
Current smoker | 336 (5.2) |
Former smoker | 458 (7.1) |
Alcohol consumption status (n, %) | |
Nondrinker | 4633 (72.0) |
Current drinker | 1464 (22.7) |
Former drinker | 341 (5.3) |
BRAFV600E mutational status (n, %) | |
Wild type | 1336 (20.8) |
Mutant | 5102 (79.2) |
Surgical extent | |
Less than total thyroidectomy | 2527 (39.3) |
Total thyroidectomy | 3911 (60.7) |
BMI, body mass index; BRAF, B-type Raf kinase; IQR, interquartile range.
Table 2 shows the comparison of the clinicopathological characteristics according to primary tumor size. BRAFV600E mutational status significantly differed by primary tumor size (P = 0.003) and was detected in 3395 (80.3%) and 1707 (77.2%) patients with a primary tumor size ≤1 cm and >1 cm, respectively. Additionally, age, gender, height, weight, BMI, smoking status, and alcohol consumption status significantly differed by primary tumor size.
Clinicopathological characteristics according to primary tumor size.
Primary tumor size | |||
---|---|---|---|
≤1 cm (n = 4226) | >1 cm (n = 2212) | P | |
Age, years (median, IQR) | 47 (39–54.3) | 46 (36–55) | 0.001 |
Gender (n, %) | |||
Female | 3332 (78.8) | 1622 (73.3) | <0.001 |
Male | 894 (21.2) | 590 (26.7) | |
Height, cm (median, IQR) | 160 (155.6–165.4) | 161 (155.9–167.4) | 0.001 |
Weight, kg (median, IQR) | 60.3 (54.3–68.5) | 61.9 (55.0–71.1) | 0.001 |
BMI, kg/m2 (median, IQR) | 23.7 (21.6–26.0) | 24.0 (21.7–26.4) | 0.003 |
Primary tumor size, cm (median, IQR) | 0.6 (0.5–0.8) | 1.5 (1.2–2.0) | <0.001 |
N stage | |||
N0/Nx | 2898 (68.6) | 834 (37.7) | <0.001 |
N1a | 1111 (26.3) | 873 (39.5) | |
N1b | 217 (5.1) | 505 (22.8) | |
Smoking status (n, %) | |||
Never smoker | 3740 (88.5) | 1904 (86.1) | <0.001 |
Current smoker | 228 (5.4) | 108 (4.9) | |
Former smoker | 258 (6.1) | 200 (9.0) | |
Alcohol consumption status (n, %) | |||
Nondrinker | 3073 (72.7) | 1560 (70.5) | <0.001 |
Current drinker | 965 (22.8) | 499 (22.6) | |
Former drinker | 188 (4.4) | 153 (6.9) | |
BRAFV600E mutational status (n, %) | |||
Wild type | 831 (19.7) | 505 (22.8) | 0.003 |
Mutant | 3395 (80.3) | 1707 (77.2) | |
Surgical extent | |||
Less than total thyroidectomy | 2224 (52.6) | 303 (13.7) | <0.001 |
Total thyroidectomy | 2002 (47.4) | 1909 (86.3) |
BMI, body mass index; BRAF, B-type Raf kinase; IQR, interquartile range.
The association between BMI and BRAFV600E mutational status by primary tumor size
As the baseline characteristics between primary tumor size ≤1 cm and >1 cm were significantly different, we examined the association between BMI and the BRAFV600E mutation in each group. In the primary tumor size ≤1 cm group, BMI, gender, and age did not significantly affect the BRAFV600E mutation risk. However, in the primary tumor size >1 cm group, BMI was significantly associated with the BRAFV600E mutation (OR: 1.034, P = 0.029) (Table 3). There was no significant difference between female and male genders in either group.
The association between body mass index and BRAFV600E mutation risk according to primary tumor size. Multivariate results for primary tumor size ≤1 cm were not shown because there was no significant factor.
Primary tumor size | ||||||
---|---|---|---|---|---|---|
≤1 cm | >1 cm | |||||
Univariate | P | Univariate | P | Multivariate | P | |
Age (years) | 0.995 (0.988–1.003) | 0.214 | 1.007 (0.999–1.016) | 0.083 | 1.008 (0.999–1.016) | 0.068 |
Gender | ||||||
Female | Reference | Reference | Reference | |||
Male | 1.220 (0.946–1.573) | 0.125 | 1.393 (1.033–1.878) | 0.030 | 1.284 (0.983–1.677) | 0.066 |
BMI, continuous (kg/m2) | 1.004 (0.980–1.028) | 0.740 | 1.035 (1.004–1.066) | 0.025 | 1.034 (1.003–1.065) | 0.029 |
Smoking status | ||||||
Never smoker | Reference | Reference | ||||
Current smoker | 0.886 (0.722–1.088) | 0.248 | 0.701 (0.429–1.145) | 0.156 | ||
Former smoker | 1.183 (0.772–1.814) | 0.441 | 0.872 (0.580–1.312) | 0.511 | ||
Alcohol consumption status | ||||||
Nondrinker | Reference | Reference | Reference | |||
Current drinker | 1.177 (0.786–1.762) | 0.428 | 0.762 (0.584–0.994) | 0.045 | 0.738 (0.569–0.958) | 0.023 |
Former drinker | 1.049 (0.710–1.550) | 0.811 | 0.758 (0.493–1.165) | 0.206 | 0.751 (0.496–1.138) | 0.177 |
BMI, body mass index.
Figure 1 shows the associations between BMI and the BRAFV600E mutation risk through the use of a restricted cubic spline function. The OR plots were adjusted for age, alcohol consumption status, and smoking status. In the entire cohort, the OR plot showed a positive association between BMI and the BRAFV600E mutation risk. However, after dividing patients into two groups based on primary tumor size, the OR plot was flat in the primary tumor size ≤ 1 cm group. On the other hand, the OR plot showed a strong positive association between BMI and the BRAFV600E mutation risk in the primary tumor size > 1 cm group.
Figure 2 shows OR plots stratified by primary tumor size and gender. The pattern was similar between female and male genders in the primary tumor size > 1 cm group but differed slightly in the primary tumor size ≤ 1 cm group. The OR plot showed a reverse U shape for male patients. However, gender was not a significant factor in logistic regression (OR: 1.220; 95% CI: 0.946–1.573, P = 0.125).
Discussion
This study aimed to assess the association between BMI and the BRAFV600E mutation risk in a large cohort in an iodine-sufficient area. A positive association was found between BMI and the BRAFV600E mutation among patients with a primary tumor size >1 cm. On the other hand, no significant association was seen among patients with a primary tumor size ≤1 cm. Gender was not a significant factor in either group.
Previous studies have demonstrated that a high BMI is associated with an increased risk of thyroid carcinoma (9, 20, 21). Several potential mechanisms have been proposed to explain this association, including overweight, oxidative stress, hyperinsulinemia, inflammation, and the effects of adipokines, such as leptin and adiponectin (22, 23, 24, 25). While a high BMI appears to be related to an increased likelihood of thyroid carcinoma, inconsistent results have also been reported. Recently, Shin et al. reported a nonlinear association between BMI and thyroid carcinoma risk in an Asian cohort (26). BMI was found to have a linear association with thyroid carcinoma risk in men but not women.
Obesity appears to be modestly associated with thyroid carcinoma risk, but the relationship between obesity and the BRAFV600E mutation is different. Recently, Rahman et al. reported that a high BMI was associated with an increased risk of BRAF-positive thyroid cancer compared to BRAF-negative cancer (OR 1.17) (12). However, limited evidence has been presented, especially in the Asian population. East Asia is an iodine-sufficient area, and the frequency of the BRAFV600E mutation was reported to be approximately 85.1% (27). Considering that the BRAFV600E mutation is known to be associated with iodine intake (16), different results might be obtained in studies conducted on the Asian population.
In East Asia, two retrospective cohort studies have reported on the association between BMI and the BRAFV600E mutation in PTC. Lee et al. reported that a high BMI was significantly associated with advanced stage and BRAFV600E mutational status (28). However, advanced stage might be associated with BRAF-positive thyroid cancer, rather than high BMI (29, 30). Although they demonstrated that BRAFV600E mutation was significantly associated with higher BMI (categorical), the numbers of patients in BMI < 18.5 and BMI ≥ 30 groups were too small. We should consider that dichotomization decreases measurement reliability, and categorization occurs with the loss of reliable information (31). Shi et al. reported a positive relationship between BMI and the BRAFV600E mutation in 108 PTC patients. BRAFV600E mutation was observed in 47.2% of enrolled patients. However, that study was conducted with a relatively small sample size, and they used body weight and height reported by patients at the time of diagnosis. To overcome the limitations of previous studies, we conducted this study with a large sample size and actually measured body weight and height, using BMI as a continuous factor. BRAFV600E mutational risk was adjusted for potential confounding factors for cancer, such as alcohol use and smoking.
In this study, we found a positive association between BMI and the BRAFV600E mutation among patients with a primary tumor size > 1 cm. However, there was no significant association in patients with a primary tumor size ≤ 1 cm. The reason for categorizing patients into two groups was due to differences in baseline characteristics. In Korea, the incidence of PTC has rapidly increased since 1999, mainly due to cancer screening. Although a decreasing trend has been observed since 2013, most of the enrolled patients were diagnosed before the debates on over-diagnosis in thyroid carcinoma in Korea (3, 32). In this study, 65.6% of the patients had a primary tumor size ≤1 cm. Considering that the proportion of papillary microcarcinoma (PTMC) in other countries is between 35.3% and 47.5 % (2, 33), the proportion of PTMC in this study was much higher.
Although obesity may be associated with thyroid carcinoma risk, the reason why high-BMI patients were more frequently BRAF-positive was unclear. If obesity was a predisposing factor for BRAFV600E mutation, consistent results should be obtained in other cancers associated with the BRAFV600E mutation. However, high BMI was positively associated with BRAF-negative cancer, whereas height was positively associated with BRAF-positive colorectal cancer (34). This result suggests that BMI may have a potentially different association with BRAFV600E mutation due to other factors, such as tumor type and primary tumor size.
This study observed that the association between the BRAFV600E mutation and obesity may vary according to primary tumor size. However, the underlying mechanism for these findings remains unclear. Given that various factors likely contribute to genetic alterations, further research is needed to fully understand the results of this study.
In this study, there was a negative association between current drinking and the BRAFV600E mutation when the primary tumor size was > 1 cm. The relationship between alcohol consumption and thyroid cancer remains inconclusive, but previous studies have suggested that moderate alcohol consumption may be linked to a reduced risk of thyroid cancer (35, 36, 37). To the best of our knowledge, the association between alcohol consumption and the BRAFV600E mutation in thyroid carcinoma has not been established. According to the findings of this study, alcohol consumption might have a protective effect against the BRAFV600E mutation, which is the most common oncogene in PTC. However, no significant association was observed in patients with a primary tumor size ≤1 cm, similar to the results for BMI. This result suggests that PTMC and PTC may have different susceptibility to gene-environment interactions or tumor microenvironments.
This study has several limitations. First, our study has the potential for selection bias. Although 6438 patients were enrolled, the study was conducted at a single tertiary referral center. Additionally, this study was conducted in an area with a high prevalence of the BRAFV600E mutation. Furthermore, BRAFV600E testing was not conducted in consecutive cases. During the study period, 12,867 patients with thyroid carcinoma underwent thyroid surgery at our hospital, of which 6777 patients (52.7%) underwent the BRAFV600E testing. Among them, 6558 patients with PTC were included in this study. In Korea, national health insurance does not cover BRAFV600E mutation testing, and the cost is about $100–130. Therefore, BRAFV600E testing was performed on patients who agreed to cover the cost. Second, only baseline BMI was available, and the longitudinal effect of high BMI on the BRAFV600E mutation could not be assessed. Also, other anthropometric measures that may better reflect obesity, such as waist circumference, waist-to-hip ratio, and percent body fat, were not assessed. Third, information on alcohol consumption at baseline was included, but we could not obtain information on the amount of alcohol consumed in the past or the type of alcoholic beverage because the questionnaires only included non-drinkers, current drinkers, and former drinkers. Further evidence is needed to confirm a negative association between alcohol consumption and the BRAFV600E mutation. Fourth, potential confounders of cancer incidence and stage, such as socioeconomic status, income, and educational attainment, were not included. Fifth, the exact mechanism underlying the different results obtained for primary tumor size could not be revealed in this study. Further studies are needed to fully understand this result.
Conclusions
A higher BMI is associated with an elevated risk of BRAFV600E mutation among those with primary tumor size > 1 cm. On the other hand, no significant association was found between BMI and the risk of the BRAFV600E mutation in patients with a primary tumor size ≤ 1 cm.
Declaration of interest
Hyunju Park, Jung Heo, Hyun Jin Ryu, Min-Ji Kim, Young Lyun Oh, Tae Hyuk Kim, Sun Wook Kim, and Jae Hoon Chung declare that there are no conflict of interest to disclose.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals who participated in the study. The data will be shared upon reasonable request to the corresponding author.
Author contribution statement
JHC, and HP performed study concept and design; HP performed development of methodology and drafted the manuscript; HP and M-JK performed statistical analysis; JH, HJR, THK, and SWK provided acquisition and interpretation of data; JHC reviewed and revised the paper; YLO provided technical and material support. All authors read and approved the final paper.
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