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A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.

ABSTRACT: Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized. The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations. Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features. GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 ? subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (P < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (P < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852-46.371, P = 0.007). MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.

SUBMITTER: Lee J

PROVIDER: S-EPMC4602546 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.

Lee Jandee J Seol Mi-Youn MY Jeong Seonhyang S Lee Cho Rok CR Ku Cheol Ryong CR Kang Sang-Wook SW Jeong Jong Ju JJ Shin Dong Yeob DY Nam Kee-Hyun KH Lee Eun Jig EJ Chung Woong Youn WY Jo Young Suk YS

Medicine 20150101 2

Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized. The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations. Gene set enrichment analysis (GSEA) ver ...[more]

PMID: 25590838

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Project description:BackgroundDistant metastasis (DM) is a rare event and has a negative effect on the prognosis for papillary thyroid carcinoma (PTC). The relationship between cervical lymph node metastasis and DM is complicated and unclear. This study aimed to evaluate the impact of N stage subclassification on different distant metastasis sites based on age stratification, especially for patients with papillary thyroid microcarcinoma.MethodsA total of 28,712 patient with PTC cases between 2010 and 2018 were extracted from the Surveillance, Epidemiology, and End Results database. Multivariable logistic regression analysis was utilized to adjust for confounding variables. Risk stratification, including positive lymph node number and lymph node ratio, was established by receiver operating characteristic curves to help predict DM.ResultsLung was the most common metastatic site regardless of N0, N1a disease, or N1b disease. As the N stage increased, the higher the rate of DM identified. After age stratification, only N1b disease significantly increased the risk of lung metastasis (LM; odds ratio, OR = 20.45, P < 0.001) rather than bone metastasis (BM; OR = 3.46, P > 0.05) in younger patients. However, in older patients, N1b disease significantly increased the risk of both LM (OR = 4.10, P < 0.001) and BM (OR = 2.65, P = 0.007). In patients with papillary thyroid microcarcinoma (PTMC), N1a disease did not increase the risk of DM, LM, and BM compared with N0 disease (P > 0.05). Furthermore, combined N stage with risk stratification has well performance in predicting DM (area under the curve, AUC = 0.761). Similar results were shown in PTC patients with LM (AUC = 0.770) and BM (AUC = 0.729).ConclusionOverall, the incidence of DM significantly increased with the progress of N disease after age stratification. N1a disease did not increase the risk of DM in PTMC patients, regardless of LM or BM. Combined N stage with risk stratification may be beneficial for DM prediction.

Project description:The surgical management of papillary thyroid microcarcinoma (PTMC), especially regarding the necessity of central/lateral lymph node dissection, remains controversial. This study investigated the clinicopathologic factors predictive of lymph node metastasis (LNM) in patients diagnosed with PTMC. Multivariate logistic regression analysis was used for PTMC patients identified from the Surveillance, Epidemiology, and End Results database who were treated by surgery between 2002 and 2012, to determine the association of clinicopathologic factors with LNM. According to the results, a total of 31,017 patients met the inclusion criteria of the study. Final histology confirmed 2,135 (6.9%) cases of N1a disease and 1,684 cases (5.4%) of N1b disease. Our multivariate logistic regression analysis identified variables associated with both central LNM and lateral lymph node metastasis (LLNM), including a younger age (<45 years), male sex, non-Hispanic white and other race, classical papillary histology, larger tumor size, multifocality, and extrathyroidal extension; distant metastasis was also significantly associated with LLNM. The significant predictors identified from multivariable logistic regression were integrated into a statistical model that showed that extrathyroidal extension had maximum weight in the predictive role for LNM. LLNM was validated to be a significant risk factor for cancer-specific death in Cox regression analyses, whereas central LNM failed to predict a worse cancer-specific survival according to our data. Therefore, we suggested that central lymph node dissection could be performed in certain patients with risk factors. Given the prevalence of LLNM in PTMC, a thorough inspection of the lateral compartment is recommended in PTMC patients with risk factors for precise staging; from the viewpoint of a radical treatment for tumors, prophylactic lateral lymph node dissection that aims to remove the occult lateral lymph nodes may be an option for PTMC with risk factors. Multicenter studies with long-term follow-up are recommended to better understand the risk factors and surgical management for cervical nodes in PTMC.

Dataset Information

A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.

Publications

A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.

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