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BACKGROUND Different scoring systems currently are being used to stratify patients with differentiated thyroid carcinoma (DTC) into risk groups. DTC is usually subdivided into papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). The objective of the current study was to identify those factors that predict long‐term unfavorable prognosis and to evaluate the predictive accuracy of the TNM staging system. METHODS The authors conducted a nested case–control study within the cohort of all patients (n = 5123) diagnosed with DTC in Sweden between 1958–1987 who survived at least 1 year after diagnosis. One control, matched by age at diagnosis, gender, and calendar period, was randomly selected for each case (patients who died of DTC). All patients were classified at the time of diagnosis according to the TNM staging system. The effect of prognostic factors on DTC mortality was evaluated using conditional logistic regression. RESULTS Patients with widely invasive FTC experienced a significantly higher mortality compared with PTC patients. The grade of differentiation was found to influence mortality significantly. Patients with TNM Stage IV disease had a higher mortality rate compared with patients with Stage II disease (odds ratio [OR] = 9.1; 95% confidence interval [95% CI], 5.7–14.6). Patients with lymph node metastases experienced a higher mortality (OR = 2.5; 95% CI, 1.6–4.1) and patients with distant metastasis at the time of diagnosis were found to have a nearly 7‐fold higher mortality rate (OR = 6.6; 95% CI, 4.1–10.5). Incomplete surgical excision was associated with higher mortality, particularly in patients with Stage I disease. CONCLUSIONS In the current study, the following were found to be clinically significant prognostic factors for patients with DTC: histopathologic subgroup, TNM staging including lymph node metastases and distant metastases, and completeness of the surgical excision.Cancer 2006. © 2005 American Cancer Society.

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.

Telomerase activation through induction of its catalytic component telomerase reverse transcriptase (TERT) expression is essential for malignant transformation. TERT promoter mutations namely C228T and C250T that stimulate TERT transcription and telomerase activation have recently been identified in many human malignancies. We thus determined these mutations and their biological and clinical implications in thyroid carcinomas in the present study. The TERT promoter was sequenced in 10 thyroid cancer cell lines and 144 tumors from 20 patients with anaplastic thyroid carcinoma (ATC), 51 with papillary thyroid carcinoma (PTC), 36 with follicular thyroid carcinoma (FTC), and 37 with medullary thyroid carcinoma (MTC). We identified C228T or C250T mutation in 6/8 of ATC cell lines, as well as in tumor tissue from 10/20, 13/51, 8/36 and 0/37 patients with ATC, PTC, FTC and MTC, respectively. In PTC patients, these mutations were exclusively present in the group with age >45 years (P<0.0001), and highly correlated shorter telomeres (P<0.0001) and distant metastasis (P=0.028). The previous radioactivity exposure did not induce the mutation. The presence of C228T or C250T was an independent predictor associated with shorter disease-related survival (DRS) in the entire cohort (P<0.0001), as well as among patients >45 years (P=0.021). ATC patients carrying the mutation survived shorter than those without mutations, although not statistically significant (P=0.129). The TERT promoter mutation was associated with overall survival (P=0.038) and DRS (P=0.058) of FTC patients. Taken together, age- and shorter telomere-dependent TERT promoter mutations occur frequently in follicular cell-derived thyroid carcinoma (ATC, PTC and FTC) but not in parafollicular cell-originated MTC, and may serve as a marker for aggressive disease and poor outcome.