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Overexpression of trophoblast cell surface antigen 2 is associated with BRAF V600E mutation and aggressive behavior in papillary thyroid cancer.

ABSTRACT: BACKGROUND:Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence. The dilemma in treating this cancer is how to discriminate the tumors with aggressive behavior from the indolent ones. Trophoblast cell surface antigen 2 (trop-2) has been identified in multiple epithelial cancers and proven to be associated with shortened overall survival and disease-free survival. METHODS:In this study, we retrospectively collected the clinicopathologic characteristics of 145 patients who underwent surgery at Fudan University Shanghai Cancer Center (FUSCC), and a validation cohort from The Cancer Genome Atlas (TCGA) database was identified to support the conclusion. Quantitative real-time polymerase chain reaction (qPCR) was employed to determine trop-2 mRNA in cancer tissue and adjacent normal tissue of PTC. BRAFV600E mutation analysis was determined using Sanger sequencing. The correlation of trop-2 and clinical characteristics was analyzed with Mann-Whitney U, Kruskal-Wallis, ?2, and Fisher's exact tests. RESULTS:Trop-2 overexpression was significantly associated with lymph node metastasis (LNM) (FUSCC, P<0.001; TCGA, P<0.001) and extrathyroidal extension(ETE) (FUSCC, P=0.006; TCGA, P<0.001) in both the FUSCC and TCGA cohorts. It also proved to be an independent risk factor for LNM and ETE in multivariate analysis in both cohorts. Furthermore, trop-2 expression was also associated with BRAFV600E mutation, P<0.001 in both cohorts. CONCLUSIONS:The study found that trop-2 overexpression was correlated with LNM and ETE. Additionally, it was associated with BRAF mutation, therefore, trop-2 overexpression was a potential biomarker for aggressive behaviors of PTC, also it could be an indication for targeted therapy.

SUBMITTER: Guan Q

PROVIDER: S-EPMC6962772 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Overexpression of trophoblast cell surface antigen 2 is associated with BRAF V600E mutation and aggressive behavior in papillary thyroid cancer.

Guan Qing Q Wang Yunjun Y Liao Tian T Guo Kai K Wen Duo D Wang Yu Y Xiang Jun J Wu Yi Y

International journal of clinical and experimental pathology 20180801 8

<h4>Background</h4>Papillary thyroid cancer (PTC) is the most common endocrine tumor with an increasing incidence. The dilemma in treating this cancer is how to discriminate the tumors with aggressive behavior from the indolent ones. Trophoblast cell surface antigen 2 (trop-2) has been identified in multiple epithelial cancers and proven to be associated with shortened overall survival and disease-free survival.<h4>Methods</h4>In this study, we retrospectively collected the clinicopathologic cha ...[more]

PMID: 31949805

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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.

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.

Dataset Information

Overexpression of trophoblast cell surface antigen 2 is associated with BRAF V600E mutation and aggressive behavior in papillary thyroid cancer.

Publications

Overexpression of trophoblast cell surface antigen 2 is associated with BRAF V600E mutation and aggressive behavior in papillary thyroid cancer.

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