Journal
DIAGNOSTIC PATHOLOGY
Volume 9, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/1746-1596-9-45
Keywords
BRAF(V600E) mutation; DNA methylation; Fine needle aspiration biopsy (FNAB); Thyroid nodules; Papillary thyroid cancer (PTC)
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Funding
- National Natural Science Foundation of China [81171969, 81372217]
- Fundamental Research Funds for the Central Universities
- Ph. D. Programs Foundation of Ministry of Education of China [2012021110058]
- Program for New Century Excellent Talents in University [NCET-10-0674]
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Background: Thyroid nodules with indeterminate cytological features on fine needle aspiration biopsy specimens (FNABs) have a similar to 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. Methods: Using 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. Results: BRAF(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. Conclusion: Our 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.
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