Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Dedifferentiation of Papillary Thyroid Cancer
Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Dedifferentiation of Papillary Thyroid Cancer
复制标题
DOI：
10.1210/jc.2018-02686
复制
发表时间：
2019-09-01
影响因子：
5.8
通讯作者：
Ji, Qinghai
中科院分区：
文献类型：
--
作者：
Ma, Ben;Jiang, Hongyi;Ji, Qinghai
背景：代谢重编程是肿瘤发生的共同特征。去分化甲状腺癌(DDTC)中代谢相关基因的表达模式尚不清楚。目的：本研究旨在找出一个有价值的指示乳头状甲状腺癌(PTC)去分化的标志物。设计和地点：我们使用一个发现和两个验证队列筛选出DDTC中异常的代谢基因，并进一步使用癌症基因组图谱(TCGA)队列寻找低分化的PTC表型的独立危险因素作为去分化的标志。DDTC特征的预测在TCGA队列和联合基因表达综合队列中得到了验证。我们还分析了签名风险评分与PTC临床病理特征的相关性。结果：代谢途径的显著丰富与PTC的分化状态相关。发现了包括LPCAT2、ACOT7、HSD17B8、PDE8B和ST3GAL1在内的代谢基因的特征，并在三个队列中进行了验证。该征象不仅可预测甲状腺乳头状癌，而且与BRAF(V600E)突变(P<；0.001)、T3/T4分期(P<；0.001)、甲状腺外侵犯(P<；0.001)、淋巴结转移(P<；0.001)、肿瘤/淋巴转移/转移III/IV期(P<；0.001)显著相关。LPCAT2表达下调(P=0.009)和ST3GAL1表达下调(P=0.005)增加了患者无病生存率下降的风险。结论：我们的研究结果提示代谢去调控介导了PTC的去分化，代谢基因特征可作为DDTC的生物标志物。
Context: Metabolic reprogramming is a common feature of tumorigenesis. It remains unknown concerning the expression pattern of metabolism-associated genes in dedifferentiated thyroid cancer (DDTC).Objective: This study aimed to identify a useful signature to indicate dedifferentiation of papillary thyroid cancer (PTC).Design and Setting: We used one discovery and two validation cohorts to screen out aberrant metabolic genes in DDTC, and further used The Cancer Genome Atlas (TCGA) cohort to search for independent risk factors for the low-differentiated phenotype of PTC as a signature of dedifferentiation. The prediction of the signature for DDTC was validated in the TCGA cohort and the combined Gene Expression Omnibus cohort. We also analyzed the correlations of the signature risk score with clinicopathological features of PTC. Gene set enrichment analyses were performed in the TCGA cohort.Results: Significant enrichment of metabolic pathways correlated with differentiation status of PTC. A signature of metabolic genes including LPCAT2, ACOT7, HSD17B8, PDE8B, and ST3GAL1 was discovered and validated across three cohorts. The signature was not only predictive of DDTC but also significantly associated with BRAF(V600E) mutation (P < 0.001), T3/T4 stage (P < 0.001), extrathyroidal extension (P < 0.001), lymph node metastasis (P < 0.001), and tumor/lymph node/metastasis III/IV stage (P < 0.001) in PTC. Downregulations of LPCAT2 expression (P = 0.009) and ST3GAL1 expression (P = 0.005) increased risks of decreased disease-free survival for patients. Furthermore, the signature was implicated in a number of oncogenic biological pathways.Conclusions: Our findings suggest that metabolic deregulations mediate dedifferentiation of PTC, and that the metabolic gene signature can be used as a biomarker for DDTC.