Biomarkers in Thyroid Tumor Research: New Diagnostic Tools and Potential Targets of Molecular-Based Therapy

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Thyroid cancer and nonsteroidal anti-inflammatory drug use: a pooled analysis of patients older than 40 years of age

Background: Cyclooxygenase (COX-2) has been associated with tumor growth and metastasis in several cancers, including thyroid cancer. For this reason, several investigators have studied COX-2 inhibitors in preclinical models of thyroid cancer and found antineoplastic effects. Thus, the primary aim of this study was to assess if the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of thyroid cancer. A second aim of the study was to determine additional risk or protective factors for thyroid cancer. Methods: Three large prospective population-based studies (the NIH-AARP Diet and Health Study; the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and the U.S. Radiologic Technologists Study) were pooled to investigate the association between self-reported frequency of aspirin and nonaspirin NSAID use one year prior to baseline (no use, ≤2/week, >2–6/week, and ≥7/week) and subsequent risk of thyroid cancer. A Cox regression proportional hazard model was used to estimate aggregated hazard ratios (HR) adjusted for cohort, sex, race/ethnicity, weight, smoking status, and alcohol intake. Results: There were 388,577 participants in the pooled cohort, with 481 cases of thyroid cancer. No significant risk reduction was observed with regular use of nonaspirin NSAIDs (HR = 1.14 [confidence interval (CI) 0.84–1.55]), and/or regular use of aspirin (HR = 1.06 [CI 0.82–1.39]). The multivariate regression analysis confirmed as previously reported in the literature that female sex, obesity class I (body mass index [BMI] = 30–34.99 kg/m(2)), and obesity class II (BMI = 35–35.99 kg/m(2)) were independently associated with an increased thyroid cancer risk. Current smoking status and moderate and excessive alcohol use were also confirmed as independent risk factors associated with a reduced thyroid cancer risk. Conclusions: Neither nonaspirin NSAIDs nor aspirin use is associated with a reduced risk of thyroid cancer. Women and obesity are associated with an increased risk of thyroid cancer, whereas smoking and alcohol use are associated with decreased risk of thyroid cancer

Does Familial Non-Medullary Thyroid Cancer Adversely Affect Survival?

Background: Familial non-medullary thyroid cancer (FNMTC) is associated with a higher rate of multifocality and a higher recurrence rate than sporadic thyroid cancer. However, the effect of FNMTC on life expectancy is unknown. Material and Methods: Using data from our FNMTC database, we calculated life expectancy and survival rates after diagnosis of FNMTC and compared the results with the rates for unaffected family members and for the standard US population. Overall life expectancy and survival rates were calculated using the Kaplan-Meier method. We compared patients from families with 2 affected members with patients from families with ≥3 affected members. We also compared patients diagnosed in a known familial setting (index cases and subsequent cases) with patients diagnosed before the familial setting was recognized. Results: There were 139 affected patients with 757 unaffected family members. The mean age at diagnosis was 40.8 ± 13.9 years and the mean follow-up time was 9.4 ± 11.7 years. Ten patients died of thyroid cancer during follow-up. The life expectancy of patients with FNMTC was similar to that of their unaffected family members. Survival was significantly shorter for patients with 3 or more affected family members, for patients diagnosed before the familial setting was recognized, and for patients with anaplastic cancer. Conclusions: Our results suggest that FNMTC may be more aggressive than sporadic thyroid cancer, particularly in families with 3 or more affected members. However, when recognized and treated appropriately, it does not significantly shorten the overall life expectancy of the affected patient

KIAA0101 Is Overexpressed, and Promotes Growth and Invasion in Adrenal Cancer

Background: KIAA0101 is a proliferating cell nuclear antigen-associated factor that is overexpressed in some human malignancies. Adrenocortical neoplasm is one of the most common human neoplasms for which the molecular causes are poorly understood. Moreover, it is difficult to distinguish between localized benign and malignant adrenocortical tumors. For these reasons, we studied the expression, function and possible mechanism of dysregulation of KIAA0101 in human adrenocortical neoplasm. Methodology/Principal Findings: KIAA0101 mRNA and protein expression levels were determined in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 adrenocortical carcinoma (ACC). SiRNA knockdown was used to determine the functional role of KIAA0101 on cell proliferation, cell cycle, apoptosis, soft agar anchorage independent growth and invasion in the ACC cell line, NCI-H295R. In addition, we explored the mechanism of KIAA0101 dysregulation by examining the mutational status. KIAA0101 mRNA (9.7 fold) and protein expression were significantly higher in ACC (p,0.0001). KIAA0101 had sparse protein expression in only a few normal adrenal cortex samples, which was confined to adrenocortical progenitor cells. KIAA0101 expression levels were 84 % accurate for distinguishing between ACC and normal and benign adrenocortical tumor samples. Knockdown of KIAA0101 gene expression significantly decreased anchorage independent growth by 80 % and invasion by 60 % (p = 0.001; p = 0.006). W

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN