Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAF(V) (600E) PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation.

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BRAF V600E mutation has emerged as a marker of aggressive behavior in papillary thyroid carcinoma but its significance in microcarcinoma is not entirely clear. One-hundred and twenty-nine papillary thyroid microcarcinomas were tested for BRAF V600E mutation by single-strand conformation polymorphism, and their clinicopathologic features (age, sex, tumor size, multifocality, nodal metastases, histologic subtype, tumor cell morphology, architecture, tumor-associated stromal reaction, tumor interface to non-neoplastic thyroid (well circumscribed vs infiltrative), extrathyroidal extension, lymphovascular invasion, intratumoral multinucleated giant cells, and adjacent non-neoplastic thyroid pathology) were examined. Compared with tumors without the mutation (39/129, 30%), the mutated microcarcinomas (90/129, 70%) showed significantly higher prevalence of infiltrative tumor borders (78/90 vs 23/39, P ¼ 0.001), tumor-associated stromal desmoplasia/fibrosis and/or sclerosis (80/90 vs 25/39, P ¼ 0.002), classic nuclear features of papillary thyroid carcinoma (90/90 vs 35/39, P ¼ 0.008) and cystic change (43/90 vs 11/39, P ¼ 0.05). BRAF V600E mutation was more frequent in classic (75%), tall cell (91%), and other variants (470%) than in follicular variant (21%) of papillary thyroid microcarcinoma. Tumors without the mutation were significantly more likely to be solid, well circumscribed, and lacked desmoplasia/fibrosis or sclerosis. However, on multivariate analysis, only the follicular variant of papillary microcarcinoma was significantly associated with the absence of mutation (odds ratio (95% confidence interval): 0.09 (0.01-0.54)). Lymph node metastases (n ¼ 24) were more frequent in microcarcinomas with mutation than without (21/24 vs 3/24, P ¼ 0.02). All patients with lateral cervical node metastasis (n ¼ 9), and all but one tumor with extrathyroidal extension (n ¼ 17/18) showed BRAF V600E mutation. No significant differences were noted in age, sex, tumor size, multifocality, lymphovascular invasion, psammoma bodies, stromal calcification, intratumoral multinucleated osteoclastic-type giant cells, and lymphocytic infiltration between the two groups of tumors. BRAF V600E mutation is an early event in thyroid carcinogenesis, and is associated with distinctive morphology and aggressive features even in papillary thyroid microcarcinomas.

Purpose: Epigenetic events are a critical factor contributing to cancer development.The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non^small cell lung cancer (NSCLC). Experimental Design: We used microarray analysis to screen for tumor suppressor genes. Results: We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1expression NSCLC. Conclusions: These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.Lung caner is the leading cause of cancer-related death in the United States (1, 2). Prevention, screening, and treatment of this cancer are all problematic, emphasizing the need for the development of new diagnostic and therapeutic strategies. Epigenetic events are an important normal cellular function and, as evident from recent research, are a critical force driving initiation and progression of cancer (3, 4). Recent studies show that silencing of tumor suppressor genes, resulting from epigenetic alterations, are an early event in many human malignancies, including non -small cell lung cancer (NSCLC; refs. 3,4). Epigenetic interventions, particularly those targeting histone deacetylase are among the most promising therapies for cancer, and histone deacetylase inhibitors are already being used in the clinic (5, 6). Moreover, because epigenetic changes occur early in tumorigenesis and are associated with distinctive cancer types, they could represent targets for chemoprevention and early diagnosis. These recognitions have prompted extensive research aimed at discovering silenced tumor suppressors.In the present study, we used a combined treatment of NSCLC cells with 5-aza-2 ¶-deoxycytidine (5-Aza-dC) that reverses DNA methylation and suberoylanilide hydroxamic acid (SAHA) that inhibits histone deacetylases followed by microarray analysis to identify additional tumor suppressor genes in lung cancer. After screening over 22,000 genes, we focused on Per1 for additional studies. Reduced expression of Per1 was found in a large collection of NSCLC samples. Epigenetic silencing of Per1 promoter was detected in NSCLC cell lines and overexpression of Per1 was associated with growth inhibition in these cells. The results suggest that Per1 is an epigenetically silenced tumor suppressor in lung cancer. Materials and ...