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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 mutations 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 the 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 had no or minimal effect alone, whereas coexisting BRAF/RAS and TERT mutations had a robust synergistic effect on poor clinicopathologic 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 vs 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, whereas 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.

SUBMITTER: Shen X

PROVIDER: S-EPMC5132178 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A six-genotype genetic prognostic model for papillary thyroid cancer.

Shen Xiaopei X Liu Rengyun R Xing Mingzhao M

Endocrine-related cancer 20161114 1

A unique prognostic role of the genetic duet of BRAF V600E and TERT promoter mutations 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 the interactions among the three mutations in clinical outcomes of PTC. We found that BRAF and RAS mutations were mutually exclusive, but both were associated wit ...[more]

PMID: 27875244

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Project description:BRAF mutation is a representative oncogenic mutation, with a frequency of 60% in papillary thyroid carcinoma (PTC), but the reasons for the poor prognosis and more aggressive course of BRAF-mutated PTC are controversial. Tumor immune microenvironment (TIME) is an essential factor permitting the development and progression of malignancy, but whether TIME participates in the prognosis of BRAF-mutated PTC has not yet been reported. The primary goal of the present study was to provide a comprehensive TIME-related prognostic model to increase the predictive accuracy of progression-free survival (PFS) in patients with BRAF-mutated PTC. In this study, we analyzed the mRNA-seq data and corresponding clinical data of PTC patients obtained from the TCGA database. By calculating the TIME scores (immune score, stromal score and ESTIMATE score), the BRAF mutation group (n=237) was dichotomized into the high- and low-score groups. By functional analysis of differentially expressed genes (DEGs) in different high/low score groups, we identified 2 key TIME-related genes, HTR3A and NIPAL4, which affected PFS in BRAF-mutated PTC. A risk scoring system was developed by multivariate Cox analysis based on the abovementioned 2 TIME-related genes. Then, the BRAF-mutated cohort was divided into the high- and low-risk groups using the median risk score as a cutoff. A high risk score correlated positively with a higher HTR3A/NIPAL4 expression level but negatively with PFS in BRAF-mutated PTC. Ultimately, a nomogram was constructed by combining risk score with clinical parameter (Tumor stage), and the areas under the ROC curve (AUCs) of the nomogram for predicting 1-, 3- and 5-year PFS were then calculated and found to be 0.694, 0.707 and 0.738, respectively, indicating the improved accuracy and clinical utility of the nomogram versus the risk score model in the BRAF-mutated PTC cohort. Moreover, we determined the associations between prognostic genes or risk score and immune cell infiltration by two-way ANOVA. In the high-risk score, high HTR3A expression, and high NIPAL4 expression groups, higher infiltration of immune cells was found. Collectively, these findings confirm that the nomogram is effective in predicting the outcome of BRAF-mutated PTC and will add a spatial dimension to the developing risk stratification system.

Dataset Information

A six-genotype genetic prognostic model for papillary thyroid cancer.

Publications

A six-genotype genetic prognostic model for papillary thyroid cancer.

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