Thyroid cancer is the most common endocrine malignancy with 567,000 new cases and 41,000 deaths worldwide in 2018 (1). Thyroid cancer generally derives from follicular epithelial cells. Follicular thyroid carcinoma (FTC) is the second most common thyroid cancer originating from thyroid epithelial cells following papillary thyroid carcinoma (PTC) (2).
BRAF mutation is the most common genetic alteration in PTC, accounting for approximately 60% of the alterations (3). In contrast, RAS mutation is the most prevalent oncogenic drivers in FTC (4), although recent studies using next generation sequencing (NGS) revealed novel driver mutations other than RAS such as DICER1, EIF1AX, and EZH1 (5). RAS mutation is also associated with poor prognosis in FTC. Several studies indicated that RAS-mutated FTCs were associated with poor overall survival and distant metastasis (6,7). The incidence of RAS mutation in FTC varies among studies ranging from 10.5% to 56.9%, which is higher than follicular adenoma (FA) from 8% to 48% (8,9). Some of this variation is due to the relatively small number of samples available for the studies and the use of different methodologies (9). Moreover, some researchers tried to explain the geographical difference in the incidence of RAS mutation in terms of iodine intake of the populations. The results remain controversial (10,11).
Some oncogenic genetic rearrangements also contribute to tumorigenesis in follicular thyroid neoplasms, and PAX8/PPARγ rearrangement is the most common in FTC and FA at about 30% and 10% occurrence (12). This gene rearrangement results in the production of the PAX8/PPARγ fusion protein which acts as an oncoprotein by inhibiting endogenous PPARγ activity, although the mechanisms of tumorigenesis induced by this fusion gene are not fully understood (13). Other chromosomal rearrangements including DERL-COX6C and CREB3L2-PPARγ make up only a subset of FTCs (14). Recent large cohort studies suggested that PAX8/PPARγ did not correlate with invasiveness or affect prognosis in FTC (15). Geographical differences in the incidence of PAX8/PPARγ rearrangement in FTC is better recognized than RAS mutation in FTC. Interestingly, PAX8/PPARγ rearrangement is considered to be much more common in Western countries than in Asia. This may be attributed to ethnic differences, iodine intake, or radiation exposure, but there is no definitive conclusion (16-18).
The genetic alterations in thyroid cancer have received attention as possible diagnostic or treatment targets (4). However, when adopting therapeutic or diagnostic strategies based on molecular information, there should be careful consideration of the various genetic backgrounds of different populations, especially in Asian and Western countries. Although there are studies on the frequency of RAS mutation and PAX8/PPARγ rearrangement in FTC from various regions, worldwide comprehensive information is still limited. Grasping world trends of genetic backgrounds in FTC is important for the sake of clinical practice. Therefore, we systematically reviewed the available literature on the subject with the goal of creating a global mutational map of FTC. We present the following article in accordance with the PRISMA reporting checklist (available at http://dx.doi.org/10.21037/gs-20-356).
We searched the electronic databases of PubMed, Web of Science for relevant English papers from the inception in 1987 to September 2019 using the following search terms: (follicular OR follicular thyroid) AND (carcinoma OR cancer OR tumor) AND (RAS OR NRAS OR HRAS OR KRAS OR PAX8 OR PPARγ). Additionally, we performed a manual search by reviewing the citations within the included publications and reviews. Our study protocol generally followed the recommendation of the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement (19).
Selection criteria and abstract screening
We imported all search results from each electronic database into EndNote (Clarivate Analytics, PA, USA) and deleted duplicates. Two reviewers independently screened titles and abstracts of included studies (TO and HGV). We only included studies in the final analysis that contained information on the frequency of any of the RAS mutations or the PAX8/PPARγ fusion gene in FTC. We did not include the studies dealing with only borderline tumors introduced by recent WHO classification such as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), follicular tumor of uncertain malignant potential (FT-UMP), and well-differentiated tumor of uncertain malignant potential (WDT-UMP) (20). The exclusion criteria were (I) studies on thyroid tumors other than FTC including Hurthle cell carcinoma which was previously considered an oncocytic variant of FTC; and (II) case reports, reviews, editorial papers, conference and meeting abstracts, or books. The 2 reviewers resolved any discrepancies between them through discussion and consensus.
Subsequently, the reviewers read the full text of all potential articles and excluded many from our study. After completing the selection of articles, we extracted the data into a standardized extraction form. Any disagreements were solved, again, by discussion and consensus. The data extracted from the studies included information about the institutions, country, year of publication, admission period of the study, mutation detecting methods, type of samples, study design, age, gender, and frequency of genetic alterations. Extracted genetic alterations were exon 1 or exon 2 mutation of each RAS gene and PAX8/PPARγ rearrangement.
Statistical analyses were conducted using the GraphPad Prism 8 software (GraphPad software, San Diego California, USA). Categorical variables were compared using the Pearson chi-square test. A P value <0.05 was considered statistically significant.
We found 1,329 articles through title and abstract screening and selected 144 of them for full-text reading. After reading these articles’ full texts, we excluded 73 studies for the following reasons: (I) inability to extract frequency data of genetic alterations, (II) number of FTC samples in the study was less than 5 FTCs and inadequate for estimating frequency, (III) the study focused on specific FTCs such as radiation induced or FTCs with distant metastases, (IV) no information as to country of samples, (V) not an English language paper, and (VI) overlapping data between the studies. We used the remaining 71 studies that included data of at least one genetic alteration in our final analysis (Figure 1). The characteristics of all included studies are listed in Table 1.
RAS mutation frequency in FTC patients by geographic region
There were 54 articles with a combined 1,143 FTC patients available for calculating the frequency of RAS mutation. These included 19 studies from Asia (5,6,10,21-34,36,37), 21 studies from Europe (11,39-41,43,46-53,55-60,63,65), 12 studies from North America (11,67-77), 1 study from Oceania (83) and 1 study from the Middle East (38). We extracted the data on each RAS mutation, including NRAS, HRAS and KRAS, from these articles and then calculated the frequency of FTC patients who had a RAS mutation. Table 2 and Figure 2A show the worldwide frequency of RAS mutation. NRAS mutation is the most frequent in all regions, followed by HRAS and KRAS mutation.
Most of the Asian countries had a greater than 30% prevalence of RAS mutation, while some European countries such as Germany (8%), Portugal (12%) and Turkey (0%) had much lower frequencies. In North America, RAS mutation was relatively high (28%). Although the frequency of NRAS and HRAS mutation was not different between Asian and European countries (24% vs. 21%, P=0.22 and 7% vs. 7%, P=0.71, respectively), Asian countries had a slightly higher KRAS mutation frequency than Western countries (5% vs. 2%, P=0.016), and as a whole, the frequency of RAS mutation in Asian countries was statistically higher than Western countries (34% vs. 27%, P=0.006) (Table 3).
We thought that differences in the studies’ detection methods might influence the reported RAS mutation frequencies. Therefore, we performed a subgroup analysis incorporating studies using the direct sequencing method which is a gold standard for mutation detection and is the most prevalent method in our collection of studies. We found 21 studies with 534 FTC patients and divided them into Asian and Western countries. In the subgroup analysis, there was no statistical difference in RAS mutation frequency between Asian and Western countries (28% vs. 25%, P=0.47) (Table 4).
PAX8/PPARγ rearrangement in FTC patients by geographic region
There were 39 articles with 764 FTC patients available for calculating the frequency of PAX8/PPARγ rearrangement. These included 8 studies from Asia (5,16,17,26,28,33-35), 17 studies from Europe (15,41-45,51-54,56,61-66), 11 studies from North America (68,71-74,76-81), 1 study from South America (82), and 2 studies from Oceania (83,84). Table 2 and Figure 2B show the frequencies of PAX8/PPARγ rearrangement. In Asian countries, the frequency of PAX8/PPARγ rearrangement is low, ranging from 2% to 11%. In North America, (all studies were from USA) the frequency was high (32%). On the other hand, European countries had a variety of frequencies among countries. Germany, Italy, Poland and Norway had relatively low frequencies, less than 5%, but France, Portugal and Croatia had greater than 30% frequency. As a whole, Western countries had a higher prevalence of PAX8/PPARγ rearrangement than Asian countries (23% vs. 4%, P<0.001) (Table 3).
In our systematic review, we studied the geographical distribution of two representative genetic alterations in FTC and highlighted the similarities and differences between Asian and Western countries. Our study included all available published articles creating a comprehensive worldwide review focusing on the frequency of genetic alterations in FTC. Our results showed that RAS mutation in Asia is significantly more prevalent than in Western countries, although the difference disappeared in our subgroup analysis that only incorporating studies using direct sequencing method. We also showed that the incidence of PAX8/PPARγ rearrangement in the West was much higher than that found in Asia.
Our literature review showed that the reported frequencies of RAS mutation and PAX8/PPARγ rearrangement in FTC vary widely, with RAS mutation ranging from 0 to 57% and PAX8/PPARγ rearrangement ranging from 0 to 62%. There are several hypotheses as to why there is such variation, and the method of detecting these mutations might especially influence the data collected on mutational frequency in these studies (9). Vasko et al. reported that direct sequencing detected RAS mutation less frequently than other methods because direct sequencing is unable to detect small numbers of mutated alleles in samples (85).
Our study includes various kinds of detection methods for RAS mutation including direct sequencing, real-time quantitative PCR, allele specific PCR, allele-specific oligonucleotide hybridization (ASO), next generation sequencing (NGS), pyrosequencing, PCR-restriction fragment length polymorphism (RFLP), PCR-primer introduced restriction with enrichment for mutant alleles (PIREMA), multiplex PCR and liquid bead array assay. In our first analysis of the data, we did not consider the methodological differences between studies, and we found that differences in RAS mutation frequency was consistent with a previous report (8). However, our subsequent subgroup analysis that was limited to studies using the direct sequencing method resulted in no statistical difference in RAS mutation incidence between Asian and Western countries. This result implies that the difference between Asian and Western countries in RAS mutation frequency does not exist or is lower than previously thought. Western countries tend to use more varied types of methodology for detecting mutations than do Asian countries. Direct sequencing was the method used in 52% (10/19) of the studies from Asian countries but only 34% (9/26) of the studies from Western countries (Table 1). Detection methodology other than direct sequencing might decrease the apparent mutation frequency of RAS mutation in Western countries. In contrast to RAS mutation, the detection method of PAX8/PPARγ rearrangement is generally limited; almost all the studies used either reverse-transcription PCR (RT-PCR) or fluorescence in situ hybridization (FISH). Dwight et al. (66) reported slightly higher detection rates with FISH while Klemke et al. (44) reported that RT-PCR could detect PAX8/PPARγ rearrangement better than FISH. There was not a large difference between RT-PCR and FISH for detecting PAX8/PPARγ rearrangement, although there were several discrepant results. Even though studies from Asian countries adopted both the FISH and RT-PCR methods, the incidence of PAX8/PPARγ rearrangement is consistently low, ranging from 0 to 10%. Therefore, it seems that factors other than detection methodology must account for the difference between Asian and Western countries in the incidence of PAX8/PPARγ rearrangement in FTC.
There is a discussion as to the relationship between iodine intake and thyroid cancer. Iodine intake is considered a factor in the occurrence of thyroid cancers and also the manner of tumorigenesis itself. The association between a high BRAF mutation ratio in PTC and a high iodine intake has been investigated and involves some controversy: Guan et al. (86) reported that a high iodine intake increased the BRAF mutation in PTC in the Chinese population, whereas other studies showed no association between iodine intake and BRAF mutation in PTC (10,87). In FTC, the association between RAS mutation and iodine intake is also disputed. Some authors concluded that there was no association between the amount of iodine ingested and RAS mutation in FTC (10,88) while others reported a tendency for higher rates of RAS mutation with low iodine intake (11). At present, to the best of our knowledge, there are no reports that examined the association between PAX8/PPARγ rearrangement and iodine intake. The studies reporting on the frequency of PAX8/PPARγ in Asia are mainly from Japan and Korea where the iodine intake is high. Therefore, it is possible that the high incidence of PAX8/PPARγ rearrangement in this region is due to the large amount of iodine ingested. However, iodine intake alone cannot explain the wide range of frequencies among Western countries where most populations have average iodine intakes (89). Iodine intake does not appear to be a definitive factor for the incidence of PAX8/PPARγ rearrangement.
It is well documented that radiation exposure can induce thyroid cancer. The main risk factors for the development of thyroid cancer are the radiation dose and the age at exposure (90). Radiation exposure is also known to affect the mechanism of carcinogenesis of thyroid cancer by causing a specific type of genetic rearrangement (91). Specific fusion genes are associated with a particular histologic type of PTC. The solid variant of PTC often harbors RET/PTC3 rearrangements while RET/PTC1 rearrangements are associated with the classical type of PTC (92). The occurrence of PAX8/PPARγ rearrangement is also reported in radiation-induced PTCs (93). However, information on the association between genetic alterations in FTC and radiation exposure are limited mainly due to the low incidence of radiation-induced FTCs. Nikiforova et al. reported that radiation-induced FTC had higher rates of PAX8/PPARγ rearrangement (3/3, 100%), although the non-radiation-induced counterparts also had a high incidence of the rearrangement (5/12, 42%) (18). Radiation exposure might increase the frequency of PAX8/PPARγ rearrangement in FTC, but the incidence of non-radiation-induced FTC in the USA is still high compared to Asian countries. We believe that radiation exposure does not explain the difference in PAX8/PPARγ rearrangement frequency in FTC between Asia and the West. Further studies from a novel point of view would be needed to explain this regional difference.
There are several limitations in our study. First, most of the studies we included are retrospective, which might cause some selection bias. Second, heterogeneity in sample preparation (FFPE vs. frozen tissue) might affect the included studies’ results. In addition, we could not completely exclude the influence that detection methods might have had in finding the genetic mutations, although we performed a subgroup analysis to account for this. The mutation detection rates of the direct sequencing method might be affected by the institution and the technology available during the era the samples were tested. To overcome this limitation, we would need a large prospective study using consistent detection and sample preparation methods. Apart from the technical point of view, we must consider the influence of observer variation in the diagnosis. Follicular thyroid lesions with the fibrous capsule which include adenomatous goiter, follicular variant of PTC, FA, and FTC, often raise difficulties and discrepancy in diagnosis. Hirokawa et al. showed the difference in diagnostic criteria of these lesions between Japanese and American pathologists (94). Franc et al. reported the low diagnostic reproducibility of minimally invasive FTC (95). Generally, PAX8/PPARγ rearrangement and RAS mutation frequency in FTC is higher than FA (36% vs. 11% and 40% vs. 26%, respectively) (9,12). Therefore, potential histological heterogeneity of previously reported FTC cases might influence our result. Finally, we must note that prevalence of genetic events might depend on the actual prevalence of the cancer in the population. Currently, information is limited about the underlying factors that can cause FTC or induce the specific genetic alterations. A certain unknown factor in the region may contribute to the tumorigenesis of FTC and thereby increase the frequency of FTC with a specific genetic alteration. Uncovering all the factors that contribute to tumorigenesis in FTC would provide a better understanding of FTC patients’ genetic background around the world.
In conclusion, our study highlights differences and similarities in the genetic backgrounds of Asian and Western countries to create a global map of RAS mutation and PAX8/PPARγ rearrangement. We further shed light on the lack of substantial data of genetic alteration in FTC within certain regions. Understanding the genetic information surrounding ethnical differences should improve the practice of clinical medicine in the future.
We wish to thank Pam Zaber, DVM of Editdoc English Editing for her help with English editing of this Journal article.
Funding: JSPS KAKENHI (Grants-in-Aid for Scientific Research) supported this work, Grant Number 19K16583.
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.
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at http://dx.doi.org/10.21037/gs-20-356
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-356). The series “Asian and Western Practice in Thyroid Pathology: Similarities and Differences” was commissioned by the editorial office without any funding or sponsorship. To reports grants from JSPS, during the conduct of the study. 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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