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International Journal of Clinical and Experimental Pathology logoLink to International Journal of Clinical and Experimental Pathology
. 2015 Nov 1;8(11):15155–15162.

Association between BRAF and RAS mutations, and RET rearrangements and the clinical features of papillary thyroid cancer

Jie Ming 1,*, Zeming Liu 1,*, Wen Zeng 3, Yusufu Maimaiti 1, Yawen Guo 1, Xiu Nie 2, Chen Chen 1, Xiangwang Zhao 1, Lan Shi 1, Chunping Liu 1, Tao Huang 1
PMCID: PMC4713646  PMID: 26823860

Abstract

Objective: To evaluate the significance of BRAF V600E and Ras mutations, and RET rearrangements in papillary thyroid cancer (PTC) in the South central region of China. Methods: We included patients from Union hospital’s pathology archive diagnosed with PTC and meeting the criteria for BRAF mutation, RAS mutation, and RET rearrangement testing. Medical records were analyzed for BRAF and RAS mutation status, RET rearrangements (positive or negative), and a list of standardized clinicopathologic features. Results: Positive BRAF mutation was found to be significantly associated with age and extrathyroidal extension (P=0.011 and P=0.013, respectively). However, there was no significant association between BRAF mutation and sex, tumor size, histological subtype, multifocality, or accompanying nodular goiter and Hashimoto’s. On the other hand, none of these characteristics of PTC were been found to be associated with RAS mutation. Additionally, the frequency of RET rearrangements was higher in patients ≤45 years old than that in patients >45 years old. Conclusions: We demonstrated that the BRAF V600E mutation slightly correlated with the clinicopathological characteristics of PTC in the Han population. Furthermore, neither RAS mutation nor RET rearrangements were found to be associated with the clinicopathological characteristics of PTCs. Our work provides useful information on somatic mutations to predict the risk of PTC in different ethnic groups.

Keywords: Papillary thyroid cancer, BRAF, RAS, RET

Introduction

Thyroid carcinoma is the most common endocrine malignancy. Papillary thyroid cancer (PTC) accounts for majority of the thyroid carcinomas and its incidence are still on the rise [1-3]. The typical treatment for PTC includes surgery, TSH suppressive therapy, and radioactive Iodine (RAI) administration. PTC has an excellent prognosis with an average 10-year survival rate in more than 90% cases. However, disease recurrence rates remain roughly at 20% after resection, at 10-year follow-up, which is associated with increased mortality [4]. Therefore, it is important for clinicians to focus on thyroid cancer patients displaying more aggressive phenotype marked by disease recurrence or death, so that perform individual treatment. Efforts have been made to identify patients at risk of disease recurrence and develop suitable markers, such as for the detection of somatic mutations, which might aid in predicting good versus poor prognosis.

Recently, BRAF and RAS mutations as well as RET rearrangements have been given a great deal of attention as novel prognostic markers for thyroid carcinoma [5-8]. The V600E somatic mutation of the BRAF gene is the most frequent genetic alteration in patients with PTC, and plays a fundamental role in tumorigenesis of various thyroid tumors [1]. Initially it was demonstrated that BRAF-V600E maintained tumor growth in a xenograft tumor model [9]. Since then, numerous clinical studies have suggested a strong association between BRAF-V600E and poor clinicopathological outcomes of PTC, including aggressive pathological features, increased recurrence, and loss of radioiodine avidity [10]. However, some studies have demonstrated inconsistent results perhaps owing to variations in study design and differences in ethnic groups examined [11,12].

In thyroid cancer, RAS mutations are second in prevalence to BRAF mutations. RAS mutations seem to preferentially activate the PI3K-AKT pathway in thyroid tumorigenesis, as suggested by the preferential association of RAS mutations with AKT phosphorylation in thyroid cancers [13]. Activated RAS may have a role in early follicular thyroid cell tumorigenesis and RAS mutations are a common occurrence in follicular thyroid adenoma (FTA) [1]. However, there are limited studies that focus on RAS mutations in papillary thyroid cancer [13-15].

RET-PTC is the best example of gene translocation resulting in oncogenic rearrangements [1]. RET is a proto-oncogene encoding an RTK. RET-PTC occurs as a consequence of genetic recombination between the 3’ tyrosine kinase portion of RET and the 5’portion of a partner gene. Sapio et al. found a correlation between the presence of RET-PTC and a high growth rate of benign thyroid tumors [16]. However, the role of RET-PTC in early thyroid tumorigenesis remains unclear.

Currently, there is still controversy over the association between BRAF and RAS mutations, and RET rearrangements with the poor clinicopathological features of PTC. Furthermore, previous work often studied these gene mutations in PTCs separately. In our study, we attempted to analyze the relationship between these three gene mutations, together, with the clinicopathological characteristics of PTCs in the Han population to demonstrate the association between somatic mutation and clinicopathological features.

Materials and methods

The department of pathology at Union Hospital began to perform routine BRAF V600E testing of PTC tumor specimens larger than 0.4 cm in July 2014. We identified 64 patients as having had BRAF testing of thyroid specimens. We included all patients with PTC who underwent total thyroidectomy with routine central lymph node dissection between July 2014 and July 2015. This retrospective study was approved by the ethics committees of the Union Hospital.

Medical records of all patients were reviewed for BRAF, RAS, and RET status, age, sex, tumor size, extrathyroidal extension, infiltration, distant metastasis, multicentricity, accompanying disease (Hashimoto’s, simple goiter), lymph node status, and final TNM stage.

BRAF testing

DNA was extracted from each sample using a commercial kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. A portion of BRAF exon 15 encompassing codon 600 was amplified using polymerase chain reaction (PCR) with specific primers, and amplification of codon 600 was analyzed with fluorescence-labeled hybridization probes in a real-time LightCycler 480 PCR (Applied Biosystems) melting curve assay A melting temperature of approximately 65°C corresponded with the wild-type sequence, while melting at approximately 60°C indicates the T to A transversion at nucleotide 1799 that results in the V600E mutation. This assay was validated to have sensitivity for V600E mutation detection down to a minimum of at least 25% tumor cells in the specimen.

RAS testing

Mutational analysis of RAS (HRAS, KRAS, and NRAS) in codons 12, 13, and 61, respectively, was performed using a loop-hybrid mobility shift assay (LH-MSA). DNA was extracted from thinly-sliced formalin-fixed and paraffin-embedded tumor samples using a Pinpoint slide DNA isolation system. Briefly, the deparaffinized tissues were digested with proteinase-K followed by heat inactivation at 95°C for 10 minutes, and directly subjected to polymerase chain reaction (PCR) with primers designed to amplify genomic DNA, including the site to be examined. At the end of 45 PCR cycles, the 72-merloop-hybrid generator, specific to each mutation, was added to the reaction mixture at a final concentration of 500 nM and processed using heat-denaturation followed by an annealing step to generate loop-hybrids. The final PCR products were separated on native 10% polyacrylamide gels (ATTO, Inc.). After electrophoresis, the gels were stained with SYBRGreen I (Cambrex Bio Science), and the DNA bands were detected using a Storm 860 laser-scanning imager (GE Health Care BioScience). The gene mutations were identified as mobility-shifted loop-hybrid bands. Each LH-G is a single-strand oligonucleotide with an artificial internal 10-nucleotide deletion that generates a small loop in the hybridized complementary strand adjacent to the mutated nucleotides. The PCR products found to contain mutated loop-hybrid bands, as determined by LH-MSA, were further confirmed by direct sequencing with the 3130 Genetic Analyzer (Applied Biosystems/Life Technologies).

Detection of RET/PTC rearrangements

Total RNA was extracted from the tumor specimens using the guanidine thiocyanate-phenol-chloroform method. The integrity of the RNA was verified by denaturing gel electrophoresis. Total RNA was reverse-transcribed into cDNA using the Promega reverse transcription (RT) system (Promega, Madison, WI). Nested RT-PCR was used to amplify transcripts of RET/PTC rearrangements. The resulting PCR products were analyzed by gel electrophoresis and directly sequenced with the 3130 Genetic Analyzer (Applied Biosystems/Life Technologies). GAPDH cDNA was used as an internal control for RNA quality.

Statistical analysis

Continuous variables were presented as mean ± standard deviation (SD); discrete variables were reported as a proportion and analyzed by the chi-square test or Fisher’s exact test where appropriate.

Variables associated with BRAF V600E mutation at P<.10 were used in a multivariate logistic regression model for BRAF mutation positivity. All statistical analyses were performed using SPSS software, version 13.0 (SPSS, Chicago, IL). All p values were 2-tailed, and P<.05 was considered statistically significant.

Results

Distribution of BRAF mutation, RAS mutation and RET rearrangements

A total of 64 patients with PTC from our institution met the inclusion criteria (Table 1). A total of 33 (51.6%) were positive for the BRAF mutation, and 31 (48.4%) tested negative. Only 2 (3.1%) of the patients were positive for RAS mutation, and 62 (96.9%) tested negative. There were 9 (14.1%) cases that tested positive for RET rearrangement, while most of the cases (85.9%) were negative (Table 2).

Table 1.

Clinicopathologic characteristics of the 64 patients with papillary thyroid carcinoma in the study population

Characteristic No. (%)
Age at diagnosis, y
    <45 39 (60.9%)
    ≥45 25 (39.1%)
Sex
    Female 42 (65.5%)
    Male 22 (34.4%)
Tumor size, cm
    ≤1 45 (70.3%)
    >2 19 (29.7%)
Histologic subtype
    Classic type 38 (59.4%)
    Follicular variant or other 26 (40.6%)
Multifocality
    Absent 30 (46.9%)
    Present 34 (53.1%)
Extrathyroidal extension
    Absent 19 (29.7%)
    Present 45 (70.3%)
Lymph node involvement
    Absent 34 (53.1%)
    Present 30 (46.9%)
Infiltration
    Absent 53 (82.8%)
    Present 11 (17.2%)
Distant metastasis
    Absent 57 (89.1%)
    Present 7 (10.9%)
TNM stagea
    I-II 49 (76.6%)
    III-IV 15 (23.4%)
Accompanying nodular goiter
    Absent 52 (81.3%)
    Present 12 (18.3%)
Accompanying Hashimoto
    Absent 49 (76.6%)
    Present 15 (23.4%)
a

Based on criteria established by American Joint Cancer Committee-Union.

Internationale Contre le Cancer, Seventh Edition, Staging System.

Table 2.

Mutation status of the 64 patients with papillary thyroid carcinoma in the study population

Mutation types No. (%)
BRAF mutation
    Absent 31 (48.4%)
    Present 33 (51.6%)
RAS mutation
    Absent 62 (96.9%)
    Present 2 (3.1%)
RET rearrangements
    Absent 55 (85.9%)
    Present 9 (14.1%)

When we listed the details of these three gene mutations, we found that the BRAF+RAS-RET- group occupied the highest proportion at 30%. The BRAF-RAS-RET- group was about 24%, while the other subgroup was 0%-7% (Table 3).

Table 3.

Details about the three gene mutations

BRAF mutation RAS mutation RET rearrangements Number, %
+ + + 1 (1.6%)
+ + - 1 (1.6%)
+ - + 1 (1.6%)
- + + 0 (0%)
+ - - 30 (46.9%)
- + - 0 (0%)
- - + 7 (10.9%)
- - - 24 (37.5%)

Demographic and tumor characteristics

A significantly higher proportion of elderly patients (>45 years) was found to be BRAF mutation positive (P=0.011). A similar outcome was see for the association between BRAF mutation and extrathyroidal extension (P=0.013) (Table 4), and these associations remained significant in multivariate analysis (both P=0.010) (Table 5). However, there was no significant association between BRAF mutation and sex, tumor size, histological subtype, multifocality, accompanying nodular goiter or Hashimoto’s. On the other hand, none of the characteristics of PTC were found to be associated with RAS mutation. Furthermore, patients ≤45 years old were found to have more frequent RET rearrangements than in the patients >45 years old.

Table 4.

Clinicopathologic features of papillary thyroid carcinoma with and without the BRAF V600E mutation, RAS mutation, RET rearrangements

BRAF mutation, No. (%) RAS mutation, No. (%) RET rearrangements

Characteristics Negative Positive P value Negative Positive P value Negative Positive P value
Age at diagnosis, y
    ≤45 24 15 0.011 38 1 1.00 30 9 0.009
    >45 7 18 24 1 25 0
Sex
    Female 22 20 0.438 40 2 0.542 35 7 0.707
    Male 9 13 22 0 20 2
Tumor size, cm
    ≤1 21 24 0.786 43 5 1.000 39 6 1.000
    >1 10 9 19 0 16 3
Histologic subtype
    Classic type 19 19 0.803 36 2 0.510 31 7 0.291
    Follicular variant or other 12 14 26 0 24 2
Multifocality
    Absent 16 14 0.462 29 1 1.000 24 6 0.285
    Present 15 19 33 1 31 3
Extrathyroidal extension
    Absent 13 6 0.013 19 0 1.000 18 1 0.260
    Present 18 27 43 2 37 8
Lymph node involvement
    Absent 19 15 0.222 33 1 1.000 32 2 0.071
    Present 12 18 29 1 23 7
Infiltration
    Absent 28 25 0.186 52 1 0.316 47 6 0.177
    Present 3 8 10 1 8 3
Distant metastasis
    Absent 28 29 1.000 55 2 1.000 50 7 0.253
    Present 3 4 7 0 5 2
TNM stagea
    I-II 23 26 0.665 47 2 1.000 42 7 1.000
    III-IV 8 7 15 0 13 2
Accompanying nodular goiter
    Absent 25 27 0.904 51 1 0.342 44 8 0.679
    Present 6 6 11 1 11 1
Accompanying Hashimoto
    Absent 22 27 0.382 47 2 1.000 43 6 0.427
    Present 9 6 15 0 12 3
a

Based on criteria established by American Joint Cancer Committee-Union.

Internationale Contre le Cancer, Seventh Edition, Staging System.

Table 5.

Multivariate analysis of the association of BRAF V600E mutation and clinicopathologic features of papillary thyroid cancer

Characteristic Odds Ratio (95% CI) P value
Age
    Male 0.183 (0.050-0.669) 0.010
    Female 1 [Reference]
Extrathyroidal extension
    Present 0.208 (0.063-0.683) 0.010
    Absent 1 [Reference]

Lymph node features and metastasis

Lymph node metastasis, infiltration, distant metastasis, and TNM stage were not significantly associated with the BRAF mutation-positive group or BRAF mutation-negative group. Moreover, in our study, these tumor characteristics were not significantly associated with RAS mutation or RET rearrangements (Table 4).

Discussion

The BRAF-V600E mutant occurs in approximately 45% of PTCs [1]. The significance of BRAF and RAS mutations, and RET rearrangements in the management of PTC remains unclear and controversial [7,8,11,12,17,18]. As a result of these ambiguous results, further research on the presence of genetic mutations in papillary thyroid cancer with respect to different ethnicities and regions is necessary.

The BRAF-V600E mutation causes its constitutive activation as a serine/threonine kinase. BRAF V600E-transgenic mice were observed to developed aggressive papillary thyroid cancer [19], and a large meta-analysis uniformly support the aggressive role of the BRAF-V600E mutation in PTC [20]. However, Henke et al. illustrated that BRAF mutation was not a predictive factor of long-term outcome such as recurrence and survival in papillary thyroid carcinoma [17]. Additionally, in different ethnicities, BRAFV600E analysis presented different outcomes; Liu et al. reported that there was no correlation between BRAF V600E and any clinicopathological characteristics of papillary thyroid carcinoma in Taiwan [11]. Our findings draw a similar conclusion that BRAF mutation was not strongly correlated with the clinicopathological characteristics of papillary thyroid carcinoma.

RAS in its active state is bound with GTP. There are three isoforms of RAS: HRAS, KRAS and NRAS, and the predominantly mutated form in thyroid nodules were NRAS, which mainly involves codons 12 and 61. The intrinsic GTPase terminates RAS signaling by hydrolyzing GTP and converting RAS into an inactive GDP-bound state. RAS mutation can lead to the loss of its GTPase activity so that RAS remains in its active GTP-bound state. RAS mutations have previously been reported in follicular thyroid carcinoma or follicular thyroid adenoma [21]. However, Frattini et al. did not detect any RAS in a series of 60 PTCs [14].

In this study, RAS mutation was detected in a low proportion (3.1%) of PTCs which is similar to Frattini’s findings. The only significant finding was the extrathyroid extension and a younger age correlated with positivity for BRAF mutation. Therefore, using RAS mutation status to predict poorer clinical features of PTC should be cautiously considered.

The RET gene, which is expressed preferentially in neuroendocrine tissues such as parafollicular C cells in adults, is mapped to 10q11.2 and organized in 21 exons. PTCs that displayed oncogenic rearrangements of RET were detected in up to 35% of multicenter studies and 65% of post-Chernobyl tumors had RET rearrangements [22]. However, studies on the genotype-phenotype of RET rearrangements reported ambiguous results. Previously, RET rearrangements have been reported as an adjuvant prognostic marker useful for risk stratification of patients with medullary thyroid carcinoma [18]. While in PTC, patients with RET/PTC chimeras had no statistically significant tendency towards clinical features such as lower recurrence rate or improved survival. In this study, only age appeared to be associated with RET rearrangements. After the radioactive fallout in Chernobyl, childhood thyroid tumors in Belarus were frequency observed to be positive for RET rearrangements. Investigators generally presumed that the thyroid gland was prone to radiation-induced breaks of double-stranded DNA [23]. Therefore, even in the Han population, a history of radiation exposure may still be a significant factor to predict the risk of papillary thyroid cancer.

Sugg et al. demonstrated that RET/PTC rearrangements in young patients (<45 yr of age) with small thyroid carcinomas demonstrated a predisposition for lymphatic involvement, suggesting a possible role in the development of this subgroup of tumors [24]. In this study, we found that RET/PTC rearrangements were present in a high proportion of patients with PTCs who were less than or equal to 45 years old which was similar to Sugg’s findings. Further work focusing on RET rearrangements in younger patients in larger population with PTC should be performed in the future to verify this observation.

Some limitations, however, must be considered for our work. First, our research was a retrospective analysis where samples were received from a single center. Secondly, the number of patients with benign thyroid nodules was relatively small. In addition, long-term outcome such as recurrence and survival should still be collected for further analysis. Therefore, multicentre research, long-term follow-up, and prospective research are required to establish that these three gene mutations value for PTCs.

Conclusion

In conclusion, we demonstrated that BRAF-V600E slightly correlated with extrathyroid extension in PTC in the Han population. Furthermore, neither RAS mutation nor RET rearrangements was found out to be associated with any clinicopathological characteristics of PTCs. Our data provides useful information on somatic mutation that can aid in predicting the risk of papillary thyroid carcinoma among different ethnicities.

Disclosure of conflict of interest

None.

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