A six-genotype genetic prognostic model for papillary thyroid cancer

Abstract

A unique prognostic role of the genetic duet of BRAF V600E and TERT promoter mutation in papillary thyroid cancer (PTC) has been recently established, but the role of RAS mutation in this genetic interplay remains to be established. Using The Cancer Genome Atlas (TCGA) data of patients with PTC from 19 medical centers, we investigated interactions among the three mutations in clinical outcomes of PTC. We found that BRAF and RAS mutations were mutually exclusive but both were associated with TERT promoter mutations, with the genetic duet of BRAF/RAS and TERT mutations occurring in 34/388 (8.76%) patients. BRAF/RAS or TERT mutation each alone had no or minimal effect while coexisting BRAF/RAS and TERT mutations had a robust synergistic effect on poor clinicopatholgoic outcomes of PTC, including disease recurrence and patient mortality. For example, PTC recurrence rate was 52% with coexisting BRAF V600E/RAS and TERT promoter mutations versus 6.9% with no mutation, corresponding to a HR of 8.17 (95% CI 3.09–21.58), which remained significant at 14.71 (95% CI 2.79–77.61) after adjustment for clinicopathologic factors and institution. BRAF/RAS mutation or TERT mutation alone minimally affected Kaplan-Meier patient survival curves while the genetic duet was associated with a sharp curve decline. Thus, by confirming and expanding previous findings in single-institution studies, this multicenter data analysis establishes a six-genotype genetic prognostic model for poor outcomes of PTC with a risk order of genetic duet of BRAF V600E/RAS mutation and TERT mutation >>>> BRAF V600E = TERT mutation alone >RAS mutation alone = wild-type genes.

Transcriptome analysis of papillary thyroid cancer harboring telomerase reverse transcriptase promoter mutation

“…Compared with 348 tumors with the wild-type TERT promoter, TERT promoter mutations were associated with older age at diagnosis, larger tumor size, the presence of extrathyroidal extension, distant metastasis, more advanced TNM classification, higher MACIS score, and higher ATA risk of recurrence (Table 1). Consistent with a recent analysis, 21 TERT promoter mutation was significantly associated with a lower overall survival (log-rank P < .0001) and shorter recurrence-free survival (P = .008). The TERT promoter mutation was not associated with genetic alterations of the BRAF gene, and there was no significant difference in the percentage of BRAF-like class between the TERT promoter wild-type and mutant groups.…”

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

“…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 . It is still unclear why TERT promoter mutations most likely occur in cooperation with BRAF mutation in the same PTC.…”

“…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 ) …”

Association between TERT promoter mutations and clinical behaviors in differentiated thyroid carcinoma: a systematic review and meta-analysis

“…Among 51 studies of overall DTC, 39 [11,[14][15][16][17][18][19][20], 26 [11, 14-17, 19, 20, 26-28, 32, 35, 36, 38-41, 44, 45, 47, 48, 51, 53, 54, 56, 57], 19 [11, 14-16, 19, 20, 27, 32, 35, 36, 44, 45, 47, 48, 53, 54, 56-58], 20 [17, 19, 20, 27, 30, 31, 34-37, 40, 42, 46-48, 51, 54, 55, 59, 60], 11 [16,17,20,28,31,37,44,50,55,57,60] [16-18, 20, 27, 28, 30, 31, 33, 35-38, 42, 43, 46, 56, 58, 60, 62, 64-67], and 14 [14,16,18,20,26,28,29,39,42,46,47,60,66,68] studies were analyzed for the associations between TERT promoter mutation and gender, mean age, mean tumor size, multifocality, vascular invasion, extrathyroidal extension, LNM, distant metastasis, advanced TNM stage, persistence/recurrence, and diseasespecific mortality, respectively. Among 41 studies of PTC, 32 [11, 14-19, 27-31, 33, 35-40, 42, 43, 45-47, 49-56], 19 [11, 14-17, 19, 27, 28, 35, 36, 38-40, 45 [17, 18, 27, 28, 30, 31, 33, 35-37, 39, 42, 43, 46, 56, 58, 62, 64, 66], and 10 [14,16,…”

“…, 47, 51, 53, 54, 56], 14[11, 14-16, 19, 27, 35, 36, 45, 47, 53, 54, 56, 58], 16 [17, 19, 27, 30, 31, 35-37, 40, 42, 46, 47, 51, 54, 55, 59], 7 [16, 17, 28, 31, 37, 50, 55], 23 [14-17, 19, 27, 30, 31, 35-38, 42, 43, 45, 46, 49-52, 54, 58, 61], 32[11, 14-19, 27-31, 33, 35, 37, 38, 40, 43, 45, 46, 49-56, 58, 59, 61, 62], 15[16,17,28,29,31,32,38,39,43,45,46,50,56,62,63], 24[15- 19, 27-31, 35-40, 42, 43, 45, 46, 50, 51, 54, 56],19 …”