title: Aberrant expression of COT is related to recurrence of papillary thyroid cancer.
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.
authors: From the Department of Surgery (JL, CRL, SWK, JJJ, KHN, WYC); Department of Internal Medicine, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (SJ, CRK, DYS, EJL, YSJ); and Department of Surgery, Yonsei University Wonju College of Medicine, Kangwon (JHP), Korea.
authors: Jandee
authors: J
authors: Lee
authors: Seonhyang
authors: S
authors: Jeong
authors: Jae Hyun
authors: JH
authors: Park
authors: Cho Rok
authors: CR
authors: Lee
authors: Cheol Ryong
authors: CR
authors: Ku
authors: Sang-Wook
authors: SW
authors: Kang
authors: Jong Ju
authors: JJ
authors: Jeong
authors: Kee-Hyun
authors: KH
authors: Nam
authors: Dong Yeob
authors: DY
authors: Shin
authors: Eun Jig
authors: EJ
authors: Lee
authors: Woong Youn
authors: WY
authors: Chung
authors: Young Suk
authors: YS
authors: Jo
mesh_terms: D000328:Adult; D000367:Age Factors; D015153:Blotting, Western; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality; D004247:DNA / Q000032:analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048491:Proto-Oncogene Proteins A-raf / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality
chemical_list: D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D004247:DNA; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human