In Japanese patients with papillary thyroid carcinoma, TERT promoter mutation is associated with poor prognosis, in contrast to BRAF V600E mutation

Abstract

The prognostic value of BRAF and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR). TERT promoter mutation was found in eight patients (6 %), and this was significantly associated with total thyroidectomy, multifocality/intrathyroidal spread, lymph node metastasis and advanced stage. The BRAF mutation was found in 53 patients (38.2 %) but was not associated with any clinicopathological factors. TERT mutations were not correlated with BRAF mutation status. TERT mutation-positive tumors (TERT+) showed lower DFSR than BRAF -mutation-positive tumors (BRAF +), and TERT+/BRAF + tumors showed lower DFSR than BRAF + tumors. No cases showed loss of ATRX/DAXX expression by immunohistochemistry. TERT promoter mutations showed a lower prevalence in our series and appeared to be associated with aggressive behavior. In PTCs, telomerase activation by TERT promoter mutation might be more important than alternative lengthening of telomeres.

Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma—A meta‐analysis

“…We further excluded 11 studies that did not meet the inclusion criteria after this step. Finally, 11 studies with 3911 PTC patients were included for final analysis (Figure ) …”

“…Xing and colleagues first demonstrated that coexisting BRAF V600E and TERT promoter mutations define a group of PTCs with even worse clinicopathological outcomes . However, conflicting results were reported in other studies . The TERT promoter mutations were found to be most likely in coexistence with BRAF V600E while the number of cases harbouring TERT promoter mutations alone is very rare .…”

TERT biology and function in cancer: beyond immortalisation

“…Specifically, in thyroid cancer, our group and others reported that these mutations are associated with worse prognostic features (age of patients, tumour size and tumour stage), as well as with distant metastases, worse response to treatment and poor survival (Landa et al 2013, Liu et al 2013a,b, Melo et al 2014, George et al 2015, Qasem et al 2015, Nasirden et al 2016. TERT promoter mutations were also associated with shorter survival and/or short disease-free survival in melanomas (Griewank et al 2014, Populo et al 2014, Nagore et al 2016 and glioblastomas (Mosrati et al 2015, Simon et al 2015, Batista et al 2016, Yuan et al 2016.…”

“…Some groups report that co-occurrence of TERT promoter and BRAF mutations are associated with worse prognosis factors in thyroid cancer (Allory et al 2014, 2016a, Song et al 2016, whereas other authors have not found this association in other series (Melo et al 2014, George et al 2015, Nasirden et al 2016.…”

Overview of Hurthle cell carcinoma of thyroid

“…TSHR, thyroid-stimulating hormone receptor [38] Promotes growth and progression of thyroid cancer once initiated by oncogenic alterations SeTD2 [39] Required for DNA double-strand break repair and activation of the p53-mediated checkpoint ARID1B [40] encodes the largest subunit of the SwI/SNF chromatin re-modeling complex which has tumor suppressor activity DAXX [41] Telomere maintenance ewSR1 ewing sarcoma [42] A member of the TeT family of genes (detailed mechanism unknown) DDX6 [43] Increases messenger ribonucleic acid production MLLT4, mixed lineage leukemia [44,45] The AF-6/MLLT4 gene encodes the Afadin scaffold protein essential for epithelial integrity. Depletion of the protein markedly promotes proliferation and metastasis.…”