Prevalence of BRAF^V600E mutation in Asian series of papillary thyroid carcinoma—a contemporary systematic review

Introduction

Thyroid carcinoma is the most common endocrine malignancy that represents almost 2.1% of newly diagnosed cancer cases (1). Papillary thyroid carcinoma (PTC) is the most common histological type of differentiated thyroid carcinoma accounting for 75–85% cases, often characterized by low mortality rate and good response to radioiodine therapy (2). The 10-year overall survival rate for differentiated types of thyroid carcinoma is exceeding more than 90% (1).

Different types of thyroid cancer are characterized by different gene alterations. PTC development is closely linked to somatic point mutations in BRAF and rearrangements in RET/PTC1, RET/PTC3 and NTRK1/3 genes (2). Interestingly, driver gene aberrations in well-differentiated thyroid cancer are mutually exclusive. Rearranged during transfection (RET) gene encodes a single transmembrane tyrosine kinase receptor (3). RET/PTC fusions seem to be important in the early pathogenesis of PTC. These fusions are involved in development of 10–20% of PTC either it is sporadic or radiation-induced PTC (4,5). Other genetic alterations like RAS and PAX/PPARG are less involved in development of conventional PTC but more often associated with follicular thyroid carcinoma and follicular variant PTC (FVPTC) (2).

B-type Raf kinase (BRAF) proto-oncogene is the most common molecular target in PTC. BRAF^V600E mutation activates the protein kinase domain of BRAF that results in constitutive initiation of mitogen-activated protein kinase pathway, which in turn promotes cell growth and proliferation (5,6). Up to 10–15% of all human cancers are reported to have BRAF mutation, with a high prevalence in PTC and melanoma (7). BRAF^V600E is detected in about half of PTC cases, and may have higher rates in certain populations and histological types (2,5). In thyroid carcinoma, BRAF^V600E mutation has been shown to be associated with high risk clinicopathological characteristics, tumor recurrence, metastasis, and reduced sensitivity to radioiodine therapy (8,9). Recently, BRAF^V600E was introduced in the clinical guidelines to aid risk stratification of PTC (10).

Since BRAF mutation may serve as a diagnostic and prognostic tool, establishing a rate of BRAF on the national scale is of practical significance. Western countries have extensively reported on BRAF^V600E mutation rates in the past decade. In particular, the prevalence of BRAF^V600E mutation in the USA and Europe was ranging 35–60% (11-13). Numerous studies have recently emerged from Asian countries and regions; however, these were not sufficiently summarized to date except for showing overall high BRAF^V600E mutation prevalence in Asian PTC compared to that in Western series (14,15).

Therefore, we performed a systematic review of available literature to investigate the prevalence of BRAF mutation in series of PTC originated from various Asian countries and regions.

Methods

Search strategy

We conducted a search within three electronic databases available for all coauthors (PubMed, Google Scholar, and Scopus). Relevant articles were identified using the following combination of keywords: PTC (or cancer) and BRAF combined with the name of each Asian country. The latter was searched in the authors' affiliation. Transcontinental countries, such as Russia and Turkey were disregarded. An additional manual search was done by screening references within included publications. Furthermore, if the search in the above databases was not successful, relevant local publications were queried from the members of the Asian Working Group in Thyroid Pathology (16). We followed the recommendations of Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement (17).

Data extraction

Results of the search from all sources were imported into EndNote reference manager (Thompson Reuters, New York, NY) and two reviewers (F. R. and J. M.) independently screened the abstracts. Upon mutual agreement on eligibility of the study, both reviewers independently extracted data as per the predefined data collection sheet. The only target of our review was BRAF^V600E, therefore, other BRAF mutations were excluded from the analysis. The following information was extracted: first author, year of publication, name of institution, city, country/region, tissue type used for nucleic acid extraction, technique to detect BRAF mutation, total number of PTCs, and number of cases positive for BRAF. Therefore, clear indication of all these parameters either in the abstract or full text was qualified as inclusion criteria for our systematic review. Additional information, such as histological type of PTC, age of the cohort (e.g., pediatric), and years where study cohort belongs to, was optional but not mandatory. Baseline and clinicopathological characteristics of the patients except specified above were not required. In addition, two reviewers were asked to score and record the quality and risk of bias of the included studies. Any discrepancies during data extraction were resolved after consultation with a supervisor (A. B.) of the study. Studies not qualified as per inclusion criteria were disregarded. More exclusion criteria were as follows: (I) less than 10 cases enrolled; (II) non-primary PTC (regional and distant metastases) only and thyroid tumors other than PTC; (III) experimental and animal studies, (IV) duplicated cohorts. The latter were decided based on the overlapping of the institution name and study cohort in several publications. If potential overlap was found, a study with the largest sample size was selected.

Statistics

Descriptive statistics were calculated with Microsoft Office Excel 2010 (Microsoft, CA, USA). Further statistical analysis was performed with SPSS 23.0 statistical software package (SPSS, Chicago, IL, USA). A χ² test with Yates’s correction was applied for subgroup analysis. P value of less than 0.05 was considered to be statistically significant.

Results

Out of the total 3,966 studies identified via search in electronic libraries, only 244 met our inclusion criteria and were selected for further evaluation. Finally, after reading abstracts and full texts, 138 studies were qualified as eligible for data extraction. A flow chart of the data selection process is shown in Figure 1.

Figure 1 The PRISMA flowchart of study selection.

Asian studies classified by country and geographical region

We further separated 3 studies from Japan, China, and Saudi Arabia (18-20) in a subgroup, composed exclusively of pediatric PTCs, and focused on 135 adult or unselected series from Asian countries and regions including 40,371 PTCs. The largest datasets were provided by Japan (Table 1), South Korea (Table 2), China (Table 3), India (Table 4), and Saudi Arabia (Table 5). Summary of all 135 publications stratified by country and region of origin is shown in Table 6.

Table 1 Characteristics of included studies from Japan
Full table

Table 2 Characteristics of included studies from South Korea
Full table

Table 3 Characteristics of included studies from China
Full table

Table 4 Characteristics of included studies from India
Full table

Table 5 Characteristics of included studies from other Asian countries and regions
Full table

Table 6 Summary on BRAF rate in PTC from Asian countries and regions
Full table

Nine Japanese studies included 986 PTCs with an average BRAF rate 70.6% (Table 1). Korean series were more extensive, encompassing 20,599 PTCs in 40 studies with resultant BRAF prevalence 75.5% (Table 2). The largest number of reports were from China (n=51; 15,509 PTCs), which showed 71.2% BRAF rate (Table 3). In contrast to the countries above, Indian institutions started to report their findings quite recently, so far providing results on 561 PTCs from 9 centers across the country, averaging 45.6% prevalence of BRAF^V600E mutation (Table 4). Five studies from Saudi Arabia (mean BRAF rate 46.3%) along with less abundant reports from other Asian countries and regions, including Iran, Iraq, Kazakhstan, Myanmar, Thailand, Vietnam, Indonesia, Singapore, Taiwan, Hong Kong, and Philippines are shown in Table 5. Figure 2 summarizes BRAF prevalence on the color map. We could not find any relevant publications from such large and highly populated Asian countries as Pakistan, Bangladesh, and Malaysia.

Figure 2 Prevalence of BRAF^V600E mutation in PTC from Asian countries and regions. PTC, papillary thyroid carcinoma.

After grouping countries by geographic region, we found that the highest rate of BRAF^V600E was reported in PTC series from East Asia (76.4%). Much lower rate (45–48%) was seen in PTC cohorts originated from South Asia, Central Asia, and the Middle East while the Southeast Asian series were in between (57%). At the same time, it should be noted that the level of evidence per country demonstrated by the number of studies, number of institutions, and the total sample size was highly heterogeneous (Figure 3A,B,C). For instance, 90.2% out of all PTCs with known BRAF status were reported from China, South Korea, and Japan—countries belonging to East Asia. After adjusting the sample size to such variables as the country’s population and incidence of thyroid carcinoma, we concluded that the South Korean series provided the best evidence on BRAF mutation prevalence at the national level (Figure 3D).

Figure 3 Summary statistics of publications on BRAF mutation by country and region. (A) Total number of studies, (B) total sample size, (C) number of institutions, and (D) ratios of total sample size per annual incidence of thyroid carcinoma and total sample size per population.

Within country heterogeneity

As it could be seen from Tables 1-5 containing original data, there was a considerable heterogeneity of BRAF rate within most of the countries, the best illustrated in Japan (42–86%), South Korea (32–92%), and China (31–87%). Furthermore, such heterogeneity was found even within the same institution. For example, a group from Yamanashi, Japan reported two series of PTC with BRAF rate 42% and 82% (21,27). Similar discordances were found in studies from Sichuan, China (31% vs. 64%), Daejeon, Korea (53% vs. 89%), and others (31,44,61,65,79,90).

It is known that the detection rate of BRAF may depend on a large variety of factors. As per the data collection form, we were able to assess several of them. First, pediatric PTCs, where indicated, had lower BRAF prevalence compared to the baseline rate for the country; however this assumption was based only on a very limited number of studies with pediatric PTCs (18-20,28). Further analysis of factors potentially contributing to the within country heterogeneity was limited to China and South Korea, which had enough studies to be dichotomized by a variable of interest. We found that studies employed fresh frozen tissue and fine-needle aspirates showed a significantly higher rate of BRAF compared to those used formalin-fixed paraffin-embedded tissues (78% vs. 66% in Chinese series and 79% vs. 74% in Korean series; P<0.01). To evaluate a possibility of time trend, we divided studies into those enrolled samples before and after 2010 (only when this was indicated). It was found that the recent PTC series demonstrated a higher rate of BRAF—80% vs. 58% in Chinese series and 76% vs. 72% in Korean series (P<0.01).

Discussion

PTC is the most common malignancy of the endocrine system (153). The prevalence and annual incidence of PTC has approximately triplicated in the last three decades (154). Thyroid carcinoma ranks at the ninth place for incidence rates among all cancers (155). PTC constitutes up to 90% of thyroid carcinoma in contemporary series (156). The estimated age-standardized rate of thyroid cancer incidence in women is 3 times higher than that in men. Thyroid cancer was estimated to be the third most common malignant tumor in women in the USA and the fifth most common in Asia (157). Furthermore, the incidence rate in countries having a high human development index is 4–5 times greater than in those with the low index, while mortality rate does not differ between them (158). This is explained by the early diagnostics, advanced treatment options, and the development of the health care system in general. According to the GLOBOCAN 2018, Asia is the main continent contributing to the epidemiologic profile of thyroid cancer on a worldwide scale (157). For instance, Asia accounted for about 60% of thyroid carcinoma cases in terms of incidence, five-year prevalence, and mortality (157).

While Western opinion is dominating in the contemporary international guidelines on reporting and management of thyroid tumors, a wealth of evidence suggests that there are considerable differences between Western and Asian series of PTC, widely spanning from epidemiology and biology to specific practice patterns and treatment strategies (159-161). BRAF^V600E mutation placed on the molecular end of the spectrum is a good example of such disparity. While European and American studies reported 30–60% rate of BRAF mutation in PTC, Asian series found it to be much more prevalent (11-15).

It is important that detection of BRAF^V600E in PTC may have diagnostic significance in preoperative cytologic aspirates and also in surgical specimens (10,12,43,78,96,101,112). More recently BRAF was suggested as an important adjunct in predicting adverse prognosis in PTC, therefore getting wide recognition as a biomarker tailoring postoperative management of PTC patients (10,25). Furthermore, targeting of BRAF is considered as a promising strategy for patients with BRAF-mutant advanced thyroid cancer. In addition, recent studies found that concomitant BRAF and TERT promoter mutations in PTC patients were associated with a poor clinical outcome such as tumor aggressiveness and recurrence (162,163). Therefore, establishing a rate of BRAF on the regional and even institutional level is of practical significance. For instance, BRAF testing for rendering malignancy in preoperative thyroid fine-needle aspirates is much effective in regions with a high prevalence of BRAF mutation (39,164).

In this systematic review, we investigated a rate of BRAF mutation in a series of more than 40,000 PTCs originated from 16 Asian countries and regions, published in 2004–2020. The highest prevalence of BRAF^V600E was reported in East Asian countries (>70%), followed by Southeast Asia (57%), and a region encompassing South Asia, Central Asia, and the Middle East (<50%) (Figure 2).

With this largest series to date, we could confirm that PTCs from Asian continent, particularly from East and Southeast Asia are much more saturated with BRAF mutation than those from Europe. Studies from Eastern (Poland, Czech Republic), Central (Germany), and Southern Europe (Italy, Spain, Portugal) consistently reported BRAF prevalence in PTC below 45% (14,165-172). Series from North (USA) and South America (Brazil) also showed BRAF rate lower than in Asia (168,173,174). Although we did not perform extensive search on Western series, existing evidence based on the above studies from leading thyroid cancer centers is sufficient to illustrate a substantial difference between Asian and Western PTC.

In addition to differences among geographic regions, we found a considerable within-country heterogeneity of BRAF rate. Causes of geographic heterogeneity are multifactorial, which could be due to different etiology or study methodology, including selection bias, detection techniques, and many more. There are several etiological factors associated with the development of thyroid carcinoma, of which ionizing radiation has been the well-documented environmental cause of PTC (175). Other factors include genetic predisposition via single nucleotide polymorphisms, hormonal influence, and dietary components, such as iodine and nitrates (24,176,177). The discrepancy identified in the BRAF^V600E frequency among different regions of Asia might be due to the variation in the iodine intake. Dietary iodine intake varies in population from as low as 20 µg/d in iodine-deficient areas to as high as 1,000 µg/d in iodine-sufficient areas, where seaweed is rich in iodine, such as Japan and South Korea. Iodine intake is considered as a major risk factor for thyroid tumorigenesis especially in iodine-deficient regions (178). Thyroid follicular cells divide slowly in normal conditions but in the case of iodine deficiency, the proliferation rate of follicular cells increases due to growth of serum TSH level. Excessive proliferation of thyroid follicular cells makes their genome more susceptible to molecular alterations such as BRAF^V600E mutation. The overall incidence of histological subtypes of thyroid cancer depends upon level of iodine intake, for instance, follicular thyroid carcinoma is more prevalent in iodine-deficient areas while PTC incidence is greater in high iodine intake areas (179). In China, BRAF^V600E mutation is higher in regions where drinking water is rich in iodine compared to mildly deficient iodine intake (70). Interestingly, the most recent studies showed that both low iodine intake and excessive iodine intake served as a significant risk factor for the occurrence of BRAF mutations in the thyroid, therefore, may be risk factors for the development of PTC (63,180).

Nevertheless, we do not expect that our BRAF prevalence map (Figure 2) would match with the iodine status map due to a high complexity and interplay of all the factors that contributed to the variation of BRAF rate in different series of PTC. Our data collection protocol did not require extracting additional information about baseline characteristics of the PTC cohorts, such as age, gender, distribution of tumors by histological types, clinical stage, and other important clinicopathological variables. Further systematic review and meta-analysis studies should consider matching PTC series with the major characteristics of enrolled patients, which may help to elucidate certain tumor-specific parameters as a source of heterogeneity.

Apart from the above issues, technical aspects could greatly contribute to heterogeneity of results. We revealed that studies employed fresh frozen tissue and fine-needle aspirates showed significantly higher rates of BRAF compared to those used formalin-fixed paraffin-embedded tissues, which could be explained by the poorer DNA quality in the latter specimens. There was a wide variety of molecular methods used across the Asian studies, from a simple gel-based polymerase chain reaction (PCR) and routine Sanger sequencing to highly-sensitive real-time PCR, pyrosequencing, and next-generation sequencing. In addition, mutation-specific immunohistochemistry with VE1 antibody employed as an alternative for genotyping to detect BRAF^V600E mutation got increasing adoption in the recent studies.

All the multitude of factors described above could contribute to the geographic heterogeneity of BRAF mutation whether within Asia or between Asian and Western series. From the pathologist’s standpoint, one of the potential reasons behind the difference is the inter-observer variability in encapsulated follicular lesions between Asian and Western practices (181). Most of Western FVPTCs are classified as benign follicular adenomas or follicular carcinomas in Asia. Follicular variant of PTC is associated with RAS driver mutation (2) and sharp increase of this mutation in PTC was documented in US (173) while RAS-mutated FVPTCs are rare in Asian series (14), making the BRAF mutation rate high in Asian PTC.

This study has several limitations, which are inherently coupled with drawbacks of the original studies, including lack of data about clinicopathological characteristics of patients and histological type of PTC. Despite of the huge amount of data accumulated on BRAF mutation prevalence in Asia, more than 90% of PTCs were reported from Japan, South Korea, and China. The evidence from other countries and regions of Asia is very limited (Figure 3). Many of the studies were performed on less than 100 samples, which could not be considered sufficient to draw relevant conclusions about the nationwide rate of BRAF mutation. Our estimates suggest that 300–400 PTC cases should be enrolled to qualify a well-powered study. However, dealing with a relatively large amount of samples may be challenging in the limited resources settings, which is a case of most Asian countries. Recently we developed and validated a low-cost testing algorithm to estimate the prevalence of BRAF^V600E in large cohort studies based on mutation-specific immunostaining applied to small-sized specimens (67,142,182).

Conclusions

Our study found that the highest rate of BRAF^V600E was reported in the PTC series from East Asia (76.4%), contributed by South Korea (75.5%), China (71.2%), and Japan (70.6%). Much lower rate (45–48%) based on the limited number of studies was seen in PTC cohorts originated from South Asia, Central Asia, and the Middle East while the Southeast Asian series were in between (57%). Asian series demonstrated considerable among and within countries heterogeneity regarding the prevalence of BRAF^V600E mutation in PTC. Pooled Asian series of PTC showed a higher prevalence of BRAF^V600E than in Western series. Causes of geographic heterogeneity, whether genuine (etiology, genetics) or methodology-related (selection bias, detection techniques, and more) should be further investigated.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Kennichi Kakudo) for the series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” published in Gland Surgery. The article was sent for external peer review organized by the Guest Editor and the editorial office.

Peer Review File: Available at http://dx.doi.org/10.21037/gs-20-430

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-430). The series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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