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Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF^V600E-Mutant Advanced Papillary Thyroid Carcinoma.

ABSTRACT: The prognosis of BRAF^V600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAF^V600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAF^V600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAF^V600E-mutation (group 1), 22 had BRAF^V600E and mutation other than FGs (group 2), and 13 had BRAF^V600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39-97.58, p = 0.024). Coexistence of mutations in BRAF^V600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAF^V600E-mutant PTCs may be valuable in risk stratifying this subtype.

SUBMITTER: Song E

PROVIDER: S-EPMC8616313 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundOver the past ten years, the incidence rate of papillary thyroid carcinoma (PTC) worldwide has been increasing rapidly year by year, with the incidence rate increasing 6% annually. PTC has become the malignant tumor with the highest growth rate in the world that fourteen PTC-related mutant genes have been identified. Whether the BRAFV600E mutation related to more aggressive clinicopathologic features and worse outcome in PTC remains variable and controversial. We aim to investigate the risk factors that may predict the BRAFV600E mutation potential of these lesions and new prevention strategies in PTC patients.MethodsA total of 9,908 papillary thyroid carcinoma patients with average 74.6% BRAFV600E mutations were analyzed (RevMan 5.3 software) in this study. The PubMed, Embase, and ISI Web of Science databases were systematically searched for works published through December 15, 2021.ResultsThe following variables were associated with an increased risk of BRAFV600E mutation in PTC patients: age ≥ 45 years (OR = 1.39, 95%CI = 1.21-1.60, p < 0.00001), male gender (OR = 1.13, 95%CI = 0.99-1.28, p = 0.06), multifocality (OR = 1.22, 95%CI = 1.07-1.40, p = 0.004), lymph node metastasis (OR = 1.33, 95%CI = 0.79-2.23, p = 0.28), extrathyroidal extension + (OR = 1.61, 95%CI = 1.06-2.44, p = 0.03), vascular invasion + (OR = 2.04, 95%CI = 1.32-3.15, p = 0.001), and tumor node metastasis stage (OR = 1.61, 95%CI = 1.38-1.88, p < 0.00001). In addition, tumor size (>1 cm) (OR = 0.51, 95%CI = 0.32-0.81, p = 0.005) and distant metastasis (OR = 0.69, 95%CI = 0.22-2.21, p = 0.54) had no association or risk with BRAFV600E mutation in PTC patients.ConclusionOur systematic review identified the following significant risk factors of BRAFV600E mutation in PTC patients: age (≥45 years), gender (male), multifocality, lymph node metastasis, vascular invasion, extrathyroidal extension, and advanced tumor node metastasis stage (stages III and IV). Tumor size (>1 cm) and distant metastasis do not appear to be correlated with BRAFV600E mutation in PTC patients.

Project description:BackgroundUltrasound, cytology, and BRAFV600E mutation analysis were applied as valuable tools in the differential diagnosis of thyroid nodules. The aim of the present study was to evaluate the diagnostic efficiency of the three methods and their combined use in screening for papillary thyroid microcarcinoma (PTMC).MethodsA total of 1,081 patients with 1,157 thyroid nodules (0.5-1 cm in maximum diameter) classified as thyroid imaging reporting and data system (TIRADS) 4-5 were recruited. All patients underwent ultrasound, fine-needle aspiration (FNA) examination, and an additional BRAFV600E mutation test. TIRADS and Bethesda System for Reporting Thyroid Cytopathology (BSRTC) were adopted to judge the ultrasound and cytological results. The receiver operating characteristic (ROC) curve was established to assess the diagnostic values of different methods.ResultsOf the 1,157 nodules, 587 were benign and 570 were PTMCs. BRAFV600E mutation test had highest sensitivity (85.4%), specificity (97.1%), accuracy (91.4%), and area under the ROC curve (Az) value (0.913) among the three methods. The combination of BSRTC and BRAFV600E mutation analysis yielded a considerably high sensitivity (96.0%), accuracy (94.3%), and negative predictive value (95.9%) than either BSRTC or BRAFV600E mutation alone (P < 0.0001 for all comparisons). Of all the methods, the combined use of the three methods produced the best diagnostic performance (Az = 0.967), which was significantly higher than that (Az = 0.943) for the combination of BSRTC and BRAFV600E mutation (P < 0.0001). The diagnostic accuracy of the molecular method in the 121 nodules with indeterminate cytology was 90.1% (109/121), which was significantly higher than that of TIRADS classification, 74.4% (90/121) (P = 0.002).ConclusionThe combined use of ultrasound, cytology, and BRAFV600E mutation analysis is the most efficient and objective method for diagnosing PTMC. Both BRAFV600E mutation and TIRADS classification are potentially useful adjuncts to differentiate thyroid nodules, especially indeterminate samples classified as BSRTC III.

Project description:IMPORTANCE:BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE:To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS:Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES:Patient deaths specifically caused by PTC. RESULTS:Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE:In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

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Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF^V600E-Mutant Advanced Papillary Thyroid Carcinoma.

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Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAFV600E-Mutant Advanced Papillary Thyroid Carcinoma.

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OmicsDI is part of the ELIXIR infrastructure

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Mutation in Genes Encoding Key Functional Groups Additively Increase Mortality in Patients with BRAF^V600E-Mutant Advanced Papillary Thyroid Carcinoma.