Telomerase reverse transcriptase (TERT) promoter mutation has been reported to be associated with aggressive characteristics in differentiated thyroid cancer (DTC). This study examined the status of TERT mutation in distant metastatic DTC and evaluated the correlation between TERT mutation and radioiodine uptake, as well as that between TERT mutation and therapy response. Methods: TERT promoter and B-Raf proto-oncogene (BRAF) V600E mutation were retrospectively examined in primary tumors of 66 patients with distant metastatic DTC. Stimulated thyroglobulin (sTg) changes, radioiodine uptake status (avid or nonavid), and other imaging evidence were analyzed to evaluate therapy response. After a median follow-up of 46.5 mo (interquartile range, 29.0–70.5 mo), therapy response was classified as either disease control or refractory. Results: The prevalence of TERT mutations was 22.73% (15/66), of which C228T mutation was more prevalent (13/15) than C250T mutation (2/15). Rising sTg was noticed in 93.33% (14/15) of the TERT mutation group. Of cases negative for both mutations, 78.12% (25/32) presented with decreased sTg. TERT mutation closely correlated with a poor response to radioiodine therapy (P < 0.001), and all 15 patients were classified as refractory to radioiodine therapy, with a positive predictive value of 100% at the endpoint of follow-up. TERT mutation was associated with older mean age at diagnosis (P < 0.001), larger mean tumor diameter (P = 0.013), and greater likelihood of both BRAF mutation coexistence (P = 0.044) and radioiodine-refractory character (P < 0.001). In the 36 cases whose imaging results underwent semiquantitative analysis, TERT mutation significantly correlated with non–radioiodine avidity, with a much lower mean tumor-to-background ratio (obtained from postradioiodine whole-body scanning) than in TERT wild-type cases (P < 0.001). In addition, patients with distant metastatic DTC with TERT mutation were more likely to lose radioiodine avidity at the initial radioiodine therapy than were those with only BRAF mutation (8/8 vs. 5/11; Fisher exact test, P = 0.018). Conclusion: TERT mutation closely associates with non–radioiodine avidity in distant metastatic DTC, and when compared with BRAF mutation, TERT mutation manifested a greater negative influence on radioiodine uptake. TERT mutation could also be used as an early predictor of radioiodine-refractory cases.

Article published by the Endocrine Society Article published by the Endocrine Society

Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan–Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients.

A routine pipeline seems very common in many cancer studies that expression differentiation might be helpful in identifying prognostic molecules. There also exists a striking unanimity that molecules upregulated in cancer usually shorten survival, while downregulated ones have the opposite effect. In this study, based on the transcriptional profiles of 18 malignancies, cancer and corresponding adjacent normal tissues were used to calculate differential scores. Cox correlation coefficients of global genes were also calculated to denote survival association. The relationship between expression differentiation and survival association has been extensively studied in 18 malignancy types. Contradictory to our stereotypic research pattern, expression differentiation between cancer and adjacent normal tissues was proven irrelevant to corresponding survival correlation. Surprisingly, the more stringent cutoff we used in differentially expressed gene identification, the less prognostic information we would obtain from the collected gene groups. Moreover, the direction of dysregulated genes in cancer was irrelevant to the direction of corresponding survival correlation. Cancer-normal expression differentiation is irrelevant to genes' survival correlation in multiple cancers and, therefore, not helpful in identifying prognostic genes. For future studies, it is more sensible to look into another alternative rather than collect differentially expressed molecules in the initial step.

The relentless debate on postoperative adjuvant radiotherapy in gastric adenocarcinoma (GA) has been lasting for decades. In this study, a new biomarker, named promoter methylation burden of DNA repair genes (RPMB), was established to identify the subgroup of patients who might benefit from adjuvant radiotherapy. Methylation profiles of 397 GA tumor samples were downloaded from The Cancer Genome Atlas (TCGA). RPMB for a patient was defined as the ratio of methylated DNA repair genes to the number of all DNA repair genes. Subgroup analyses in term of overall survival (OS) and disease-free survival (DFS) indicated that most of the subgroups favored the high-RMPB group. Kaplan-Meier analysis showed that overall the patients with high RPMB after R0 resection had a significantly better clinical outcome regarding DFS (hazard ratio [HR] = 0.013, p = 0.042). Additionally, high-RPMB patients, who underwent adjuvant radiotherapy with both ≥T2 tumor and positive lymph nodes, showed superior DFS in comparison with the low-RPMB group (HR = 5.35 × 10−10, n = 26, p = 0.010). RPMB might be considered as a promising biomarker for decision-making with regard to postoperative adjuvant radiotherapy for GA patients.

Colorectal cancer is a complex multistage process following the adenoma‑carcinoma sequence. Additional research on the basis of molecular dysregulations, particularly in the precancerous stage, may provide insight into the realization of potential biomarkers and therapeutic targets for the disease. In the present study, the expression profile of human multistage colorectal mucosa tissues, including healthy, adenoma and adenocarcinoma samples, was downloaded. Genes that were consistently differentially expressed in precancerous tissues and cancer samples were collected. Based on a merged biological network, the biggest connected component composed of these identified genes and their one‑step neighbors were retrieved to conduct random walk with restart algorithm, in order to identify genes significantly affected during carcinogenesis. Therefore, 35 genes significantly affected by carcinogenic dysregulation were successfully identified. Survival and Cox analysis indicated that the expression of these genes was an independent prognostic factor confirmed by six cohorts. In summary, based on the transcription profile of multi‑stage carcinogenesis and bioinformatics analysis, 35 genes significantly associated with patient survival were successfully identified, which may serve as promising therapeutic targets for the disease.