Dataset Information

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer.

ABSTRACT:

Background

Prognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.

Methods

In patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in triplicate and stained by immunohistochemistry for RET, phospho-MEK, MAPK(dpERK), PPAR?, and phospho-AKT(pAKT). Stained slides were scored independently and blindly by two investigators and compared to tumor and patient characteristics and outcomes.

Results

A total of 231 patients had archived formalin-fixed, paraffin-embedded tumor tissue available and were included on the TMA. Mean age at diagnosis was 44 years (range 6-82 years); proportion of patients with female sex was (72%); 2015 American Thyroid Association (ATA) risk stratification was low (26%), intermediate (32%), and high (42%). BRAF V600E mutation was found in 74% of specimens, and IHC was scored as positive for RET (61%), MAPK (dpERK) (14%), PPAR? (27%), and pAKT (39%). Positive RET staining was associated with a lower risk of recurrence (HR = 0.46, 95% CI 0.22-0.96). No other molecular biomarkers were independent predictors of recurrence on univariable analysis. On RPA, patients with RET-negative and either MAPK(dpERK)-positive or pAKT-positive tumors were identified to have a high risk of recurrence (HR = 5.4, 95%CI 2.5-11.7). This profile remained associated with recurrence in a multivariable model including ATA risk stratification (HR = 2.8, 95% CI 1.3-6.0).

Conclusion

Characterization of molecular pathways involved in cPTC tumorigenesis may add further risk stratification for recurrence beyond the 2015 ATA risk categories alone.

SUBMITTER: Lin AJ

PROVIDER: S-EPMC6346248 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer.

Lin Alexander J AJ Samson Pamela P DeWees Todd T Henke Lauren L Baranski Thomas T Schwarz Julie J Pfeifer John J Grigsby Perry P Markovina Stephanie S

Cancer medicine 20181214 1

<h4>Background</h4>Prognosis among patients with differentiated thyroid cancer is widely variable. Better understanding of biologic subtypes is necessary to stratify patients and improve outcomes.<h4>Methods</h4>In patients diagnosed with classic histology papillary thyroid cancer treated from 1973 to 2009, BRAF V600E mutation status was determined on surgical tumor specimens by restriction fragment length polymorphism analysis. A tissue microarray (TMA) was constructed from tumor specimens in t ...[more]

PMID: 30552739

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Project description:Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n?=?167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P?<?0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r?=?0.4083, P?<?0.001), B- (r?=?0.2773, P?=?0.0003), and C-RAF (r?=?0.5954, P?<?0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P?<?0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P?<?0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P?<?0.001, P?=?0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P?=?0.045) and higher recurrence rate (P?=?0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066?-?21.609; P?=?0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2?±?4.1 years; P?=?0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P?<?0.0001, false discovery rate [FDR] q-value?=?0.000) and thyroid differentiation (P?=?0.048, FDR q-value?=?0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P?<?0.0001, FDR q-value?=?0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.

Project description:BackgroundCurrently, less aggressive treatment or even active surveillance of papillary thyroid microcarcinoma (PTMC) is widely accepted and recommended as a therapeutic management option. However, there are some concerns about these approaches. We investigated whether there are any demographic, clinical and ultrasound characteristics of PTMC patients that are easy to obtain and clinically available before surgery to help clinicians make proper therapeutic decisions.MethodsWe performed a retrospective chart review of 5,021 patients with thyroid tumors surgically treated in one center in 2008-2018. Finally, 182 (3.62%) PTMC patients were selected (158 (86.8%) females and 24 (13.2%) males, mean age 48.8±15.4 years). We analyzed the disease-free survival (DFS) time of the PTMC patients according to demographic and histopathological parameters. Univariate and multivariate logistic regression analyses were used to assess the relationships of demographic, clinical and ultrasound characteristics with aggressive histopathological features.ResultsAge ≥55 years, hypoechogenicity, microcalcifications, irregular tumor shape, smooth margins and high vascularity significantly increased the risk for minimal extrathyroidal extension (minETE), lymph node metastasis (LNM), and capsular and vascular invasion (p<0.0001). Multivariate logistic regression analysis demonstrated a statistically significant risk of LNM (OR = 5.98, 95% CI: 2.32-15.38, p = 0.0002) and trends toward significantly higher rates of minETE and capsular and vascular invasion (OR = 2.24, 95% CI: 0.97-5.19, p = 0.056) in patients ≥55 years than in their younger counterparts. The DFS time was significantly shorter in patients ≥55 years (p = 0.015), patients with minETE and capsular and vascular invasion (p = 0.001 for all), patients with tumor size >5 mm (p = 0.021), and patients with LNM (p = 0.002).ConclusionsThe absence of microcalcifications, irregular tumor shape, blunt margins, hypoechogenicity and high vascularity in PTMC patients below 55 years and with tumor diameters below 5 mm may allow clinicians to select individuals with a low risk of local recurrence so that they can receive less aggressive management.

Dataset Information

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer.

Background

Methods

Results

Conclusion

Publications

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer.

Similar Datasets

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