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Aberrant expression of COT is related to recurrence of papillary thyroid cancer

Authors
 Jandee Lee  ;  Seonhyang Jeong  ;  Jae Hyun Park  ;  Cho Rok Lee  ;  Cheol Ryong Ku  ;  Sang-Wook Kang  ;  Jong Ju Jeong  ;  Kee-Hyun Nam  ;  Dong Yeob Shin  ;  Eun Jig Lee  ;  Woong Youn Chung  ;  Young Suk Jo 
Citation
 Medicine, Vol.94(6) : 548, 2015 
Journal Title
 Medicine 
ISSN
 0025-7974 
Issue Date
2015
Abstract
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.
Files in This Item:
T201500350.pdf Download
DOI
10.1097/MD.0000000000000548
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Sang Wook(강상욱) ORCID logo https://orcid.org/0000-0001-5355-833X
Ku, Cheol Ryong(구철룡) ORCID logo https://orcid.org/0000-0001-8693-9630
Nam, Kee Hyun(남기현) ORCID logo https://orcid.org/0000-0002-6852-1190
Shin, Dong Yeob(신동엽) ORCID logo https://orcid.org/0000-0003-1048-7978
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Lee, Jan Dee(이잔디) ORCID logo https://orcid.org/0000-0003-4090-0049
Lee, Cho Rok(이초록) ORCID logo https://orcid.org/0000-0001-7848-3709
Jeong, Seonhyang(정선향) ORCID logo https://orcid.org/0000-0002-5549-9182
Chung, Woung Youn(정웅윤)
Jeong, Jong Ju(정종주) ORCID logo https://orcid.org/0000-0002-4155-6035
Jo, Young Suk(조영석) ORCID logo https://orcid.org/0000-0001-9926-8389
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139419
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