Role of molecular markers to predict distant metastasis in papillary thyroid carcinoma: Promising value ofTERTpromoter mutations and insignificant role ofBRAFmutations—a meta-analysis

Abstract

The presence of distant metastasis is associated with an adverse outcome in papillary thyroid cancer. We performed a meta-analysis to investigate the role of molecular markers as predictors for distant metastasis in papillary thyroid cancer. Four electronic databases including PubMed, Web of Science, Scopus, and Virtual Health Library were searched, and odds ratio and its 95% confidence interval concerning the association of BRAF, RAS, and TERT promoter mutations and RET/PTC rearrangements with distant metastasis were calculated using random-effects model. In total, 42 studies with 11,109 papillary thyroid cancers were included for meta-analyses. Overall, the presence of TERT promoter (odds ratio = 5.95; 95% confidence interval = 2.95-11.99), RAS mutations (odds ratio = 2.5; 95% confidence interval = 1.00-6.22), and RET/PTC rearrangements (odds ratio = 1.92; 95% confidence interval = 1.03-3.56) were found to be associated with a significantly increased risk for distant metastasis. BRAF mutations were not associated with an elevated risk for distant metastasis (odds ratio = 0.79; 95% confidence interval = 0.54-1.16). In conclusion, our study demonstrated the promising value of few molecular biomarkers, especially TERT promoter mutations in predicting distant metastasis in papillary thyroid cancers, while BRAF mutations showed no association with distant metastasis. Our study affirms the value of selected mutations for tumor risk stratification and assessment of patients' prognosis.

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis

“…Considering the mutually exclusive characteristic of these driving events, PTC patients may include different subtypes driven by different genomic alterations, such as BRAF mutation, gene fusion and copy number variation (CNV), which may affect patients’ predisposition to distant metastasis. The most significant genetic risk factor for DM identified in our study was gene fusion, including RET fusion, which was in agreement with previous studies 37,38 . Although due to a limited sample size (five cases), we did not find a significant association between TERT promoter mutation and DM; we, indeed, found that the mutation was associated with more malignant features, including lymph metastasis, large tumor volume and high invasiveness, which has been reported in other studies 37,39 .…”

“…The most significant genetic risk factor for DM identified in our study was gene fusion, including RET fusion, which was in agreement with previous studies 37,38 . Although due to a limited sample size (five cases), we did not find a significant association between TERT promoter mutation and DM; we, indeed, found that the mutation was associated with more malignant features, including lymph metastasis, large tumor volume and high invasiveness, which has been reported in other studies 37,39 . As to BRAF mutation, several large‐scale studies find that BRAF mutation is a risk factor for recurrence of PTC 40 or is associated with malignant clinicopathological features 41 .…”

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer

“…In this study, patients with RET positive tumor staining alone were half as likely to experience recurrence compared to patients with RET‐negative tumors. In contrast, a meta‐analysis of eight studies with 1000 patients found RET amplification through rearrangement was associated with twice the risk of distant metastasis . RET rearrangement involving the C‐terminus tyrosine kinase domain of the protein results in constitutive activation, and these fusion proteins are detected by the C‐terminal specific antibodies commonly used for IHC, including the one used in this study .…”

“…Niemeier et al created a model utilizing BRAF mutation and clinicopathologic factors for predicting extrathyroid tumor spread in papillary microcarcinomas . Most recently, a mutation in the telomerase reverse transcriptase (TERT) promoter with or without a concomitant BRAF V600E mutation was found to be associated with recurrence and cancer death risk . Several other prognostic score algorithms have been suggested, but these have not incorporated molecular analysis of tumors .…”

“…12 Most recently, a mutation in the telomerase reverse transcriptase (TERT) promoter with or without a concomitant BRAF V600E mutation was found to be associated with recurrence and cancer death risk. 13,14 Several other prognostic score algorithms have been suggested, but these have not incorporated molecular analysis of tumors. 15 An advantage of IHC over genetic analysis alone is that translated protein products and post-translational regulatory modifications such as activating phosphorylation of kinases can be qualitatively assessed.…”