KRAS mutation-driven angiopoietin 2 bestows anti-VEGF resistance in epithelial carcinomas.

Defining reliable surrogate markers and overcoming drug resistance are the most challenging issues for improving therapeutic outcomes of antiangiogenic drugs (AADs) in cancer patients. At the time of this writing, no biomarkers are clinically available to predict AAD therapeutic benefits and drug resistance. Here, we uncovered a unique mechanism of AAD resistance in epithelial carcinomas with KRAS mutations that targeted angiopoietin 2 (ANG2) to circumvent antivascular endothelial growth factor (anti-VEGF) responses. Mechanistically, KRAS mutations up-regulated the FOXC2 transcription factor that directly elevated ANG2 expression at the transcriptional level. ANG2 bestowed anti-VEGF resistance as an alternative pathway to augment VEGF-independent tumor angiogenesis. Most colorectal and pancreatic cancers with KRAS mutations were intrinsically resistant to monotherapies of anti-VEGF or anti-ANG2 drugs. However, combination therapy with anti-VEGF and anti-ANG2 drugs produced synergistic and potent anticancer effects in KRAS-mutated cancers. Together, these data demonstrate that KRAS mutations in tumors serve as a predictive marker for anti-VEGF resistance and are susceptible to combination therapy with anti-VEGF and anti-ANG2 drugs.

Generation of mega brown adipose tissue in adults by controlling brown adipocyte differentiation in vivo.

Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other ß3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM).

BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability.

Chromosome instability (CIN) is a common contributor driving the formation and progression of anaplastic thyroid cancer (ATC), but its mechanism remains unclear. The BUB1 mitotic checkpoint serine/threonine kinase (BUB1) is responsible for the alignment of mitotic chromosomes, which has not been thoroughly studied in ATC. Our research demonstrated that BUB1 was remarkably upregulated and closely related to worse progression-free survival. Knockdown of BUB1 attenuated cell viability, invasion, migration and induced cell cycle arrests, whereas overexpression of BUB1 promoted the cell cycle progression of papillary thyroid cancer cells. BUB1 knockdown remarkably repressed tumour growth and tumour formation of nude mice with ATC xenografts and suppressed tumour metastasis in a zebrafish xenograft model. Inhibition of BUB1 by its inhibitor BAY-1816032 also exhibited considerable anti-tumour activity. Further studies showed that enforced expression of BUB1 evoked CIN in ATC cells. BUB1 induced CIN through phosphorylation of KIF14 at serine1292 (Ser1292 ). Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN.

Radioiodine therapy in advanced differentiated thyroid cancer: Resistance and overcoming strategy.

Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.

The tumor ecosystem in head and neck squamous cell carcinoma and advances in ecotherapy.

The development of head and neck squamous cell carcinoma (HNSCC) is a multi-step process, and its survival depends on a complex tumor ecosystem, which not only promotes tumor growth but also helps to protect tumor cells from immune surveillance. With the advances of existing technologies and emerging models for ecosystem research, the evidence for cell-cell interplay is increasing. Herein, we discuss the recent advances in understanding the interaction between tumor cells, the major components of the HNSCC tumor ecosystem, and summarize the mechanisms of how biological and abiotic factors affect the tumor ecosystem. In addition, we review the emerging ecological treatment strategy for HNSCC based on existing studies.

[Accurate tissue flap reconstruction method based on the quadratic surface developability for head and neck soft tissue defects].

Soft tissue defects resulting from head and neck tumor resection seriously impact the physical appearance and psychological well-being of patients. The complex curvature of the human head and neck poses a formidable challenge for maxillofacial surgeons to achieve precise aesthetic and functional restoration after surgery. To this end, a normal head and neck volunteer was selected as the subject of investigation. Employing Gaussian curvature analysis, combined with mechanical constraints and principal curvature analysis methods of soft tissue clinical treatment, a precise developable/non-developable area partition map of the head and neck surface was obtained, and a non-developable surface was constructed. Subsequently, a digital design method was proposed for the repair of head and neck soft tissue defects, and an in vitro simulated surgery experiment was conducted. Clinical verification was performed on a patient with tonsil tumor, and the results demonstrated that digital technology-designed flaps improved the accuracy and aesthetic outcome of head and neck soft tissue defect repair surgery. This study validates the feasibility of digital precision repair technology for soft tissue defects after head and neck tumor resection, which effectively assists surgeons in achieving precise flap transplantation reconstruction and improves patients' postoperative satisfaction.

CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment.

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC.

GAB1 is upregulated to promote anaplastic thyroid cancer cell migration through AKT-MDR1.

Anaplastic thyroid carcinoma (ATC) represents an undifferentiated, aggressive and highly metastatic form of thyroid cancer with high mortality. GAB1, through direct interaction with the kinase PI3K and phosphatase SHP2, is tightly involved in the activation of oncogenic signals; however, the role of GAB1 in ATC remains unclear. GAB1 was significantly increased in ATC, accompanied with AKT activation. Cell proliferation, migration and invasion were impaired or enhanced by GAB1 knockdown in ATC cells or overexpression in PTC cells. Moreover, GAB1 knockdown in ATC cells inhibited and overexpression in PTC cells promoted the growth of thyroid cancer in nude mice. GAB1 mutation disrupting the interaction between GAB1 and PI3K failed to restore cell migration and invasion in GAB1-knockdown ATC cells. RNA sequencing data showed GAB1-knockdown partially reprogramed gene expression in ATC cells back to that in normal thyroid cells. MDR1 was transcriptionally regulated by GAB1, which was mediated by AKT. MDR1 was upregulated in ATC cells and MDR1 knockdown in ATC cells decreased migration and invasion. In addition, MDR1 overexpression restored cell migration and invasion and lung metastasis of GAB1-knockdown ATC cells. Collectively, GAB1 is upregulated in ATC to promote AKT activation and cellular migration and invasion through regulating MDR1 expression.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.

Novel computer-aided reconstruction of soft tissue defects following resection of oral and oropharyngeal squamous cell carcinoma.

BACKGROUND: Reconstruction of soft tissue defects following surgical tumor resection is important for quality of life in cancer patients with oral and oropharyngeal squamous cell carcinoma (SCC). This study presents a novel computer-aided reconstruction of soft tissue (CARST) technology employed with these patients. METHODS: We first described the CARST technology in detail in a report of a 34-year-old male patient with locally invasive right-sided tongue SCC following a nearly total glossectomy and reported the postoperative outcomes. This digital technology was applied to construct a 3D model from CT images, which was used to delineate surgical resection boundaries and design a personalized reconstruction of the soft tissue defect. A nonuniform rational B-spline (NURBS) was generated and applied to transform the 3D model into a 2D flap-cutting guide printed out using a 3D printer. We then reported a case-series study on oral and oropharyngeal SCC patients who were randomly assigned to receive the CARST (n = 15) or a traditional soft tissue reconstruction (n = 15). Clinicopathological features and short- and long-term postoperative outcomes between the two groups were compared. RESULTS: The patient with the tongue SCC had a successful CARST following surgical tumor resection without any complications. His speech and swallowing functions recovered well after surgery and he experienced no significant changes to his appearance following recovery. There was no recurrence within a 3-year follow-up period. Results of the case-series study showed that the CARST group had significantly shorter operative and post-operation hospital-stay time, a higher flap utilization rate, and a trend of less and milder postoperative complications, and they experienced no significant difference in intraoperative blood loss and long-term outcomes compared to the traditional group. CONCLUSION: CARST is a safer and more efficient personalized technology of soft tissue reconstruction following surgical tumor resection in patients with oral and oropharyngeal SCC.

A multicenter randomized phase II trial of hyperthermia combined with TPF induction chemotherapy compared with TPF induction chemotherapy in locally advanced resectable oral squamous cell carcinoma.

BACKGROUND: Hyperthermia has been reported to cause cancer stage regression, thus providing surgical opportunities in patients with unresectable tumors and improving the quality of life of patients by preserving certain organs. METHODS: A prospective open-label phase II trial was conducted to evaluate the efficacy of hyperthermia combined with induction chemotherapy in patients with locally advanced resectable oral squamous cell carcinoma (OSCC). Patients received hyperthermia combined with two cycles of 5-fluorouracil, cisplatin, and docetaxel (TPF) induction chemotherapy regimens or TPF induction chemotherapy alone, followed by radical surgery with postoperative radiotherapy. The primary endpoint was the clinical response rate of the induction chemotherapy. The secondary endpoints were overall survival (OS), disease-free survival (DFS), and toxicity. RESULTS: A total of 120 patients were enrolled, and 115 patients were included in the clinical response analysis. The clinical response rate was significantly higher in the experimental arm than in the control arm (65.45% vs. 40.00%, p = 0.0088). There were no unexpected toxicities, and hyperthermia and induction chemotherapy did not increase the perioperative morbidity rate. Moreover, there was a significant improvement in DFS, but no significant difference in OS between the two arms. In the subgroup analysis, increased OS and DFS rates were associated with patients with favorable clinical response after induction chemotherapy in the total population, experimental arm, and control arm. CONCLUSIONS: Our study demonstrates that hyperthermia combined with induction chemotherapy is associated with a high response rate and provides a new treatment option for patients with resectable stage III or IVA OSCC.

Immunotherapy for anaplastic thyroid carcinoma: the present and future.

Anaplastic thyroid carcinoma (ATC) is the most malignant tumor of endocrine system, which is an urgent medical problem to be solved. At present, immunotherapy studies on ATC mainly include cutting off the recruitment of tumor-associated macrophage (TAM), inducing the reprogramming of TAM and restoring its phagocytic function, targeting related immune checkpoints on T cells and natural killer cells, tumor vaccines based on oncolytic viruses and dendritic cells, and adoptive immunotherapy. Among them, immunotherapy strategies represented by targeted blocking of programmed death-1/programmed death ligand-1 at immune checkpoint have been preliminarily confirmed to benefit ATC patients, especially the combination of molecular targeted inhibitors and immunotherapy has shown excellent therapeutic effects. Due to the great heterogeneity of ATC, it is expected to provide more therapeutic strategies for patients of ATC by carrying out various immunotherapy studies including biological, immune and cellular therapies and exploring the therapeutic potential of the next generation of immune checkpoint inhibitors. This article reviews the potential immunotherapeutic targets of ATC and the progress of immunotherapy.

"Three-propulsion" suspension method for endoscopic thyroid surgery gasless axillary approach.

Gasless endoscopic thyroidectomy through unilateral axillary approach has advantages of clear vision, simple manipulation, short learning curve, hidden surgical incision, no postoperative neck scar, and less swallowing discomfort. During the procedure the separation path goes through thoracic muscle surface, sternocleidomastoid gap and jugular vein, which may meet various variations of neck muscles, blood vessels and nerves. With the "three-propulsion" suspension cavity construction method the procedure advances the dissection from the axillary incision to clavicle, from the clavicle to sternocleidomastoid gap and from the sternocleidomastoid gap to thyroid. Combined with intraoperative hanging upward hook it can establish a good cavity for the subsequent surgical operation. This article introduces the main steps, key points and attentions of the "three-propulsion"suspension cavity construction method in gasless endoscopic thyroidectomy through unilateral axillary approach.

Advances in targeted therapy for anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is a highly malignant and aggressive thyroid malignancy with rapid onset and poor prognosis. There is no effective treatment for ATC yet. Molecular targeted therapy provides a new idea for ATC treatment. Tyrosine kinase inhibitor lenvatinib has potential in treating ATC patients with favorable efficacy in clinical trials. The effectiveness of the v-raf murine sarcoma viral oncogene homologue B1 () gene inhibitor dabrafenib in combination with trametinib for the treatment of positive ATC patients has been demonstrated in clinical trials. The has proposed dabrafenib in combination with trametinib as the preferred modality for the treatment of patients with positive ATC. The immune checkpoint inhibitor pembrolizumab can be applied to treat thyroid cancer with high tumor mutational load and may be considered as the preferred modality for the treatment of ATC patients with high programmed death ligand-1 expression. The mammalian target of rapamycin pathway inhibitors, peroxisome proliferators-activated receptor γ agonists, endothelial growth factor receptors-targeting monoclonal antibody cetuximab and novel vascular blocker fosbretabulin are still in the clinical research stage, which are expected to provide new directions for the development of novel targeted drugs. This article reviews the current research progress on targeted drugs for the treatment of ATC.

Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis.

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland, with a relatively high cure rate. Distant metastasis (DM) of PTC is uncommon, but when it occurs, it significantly decreases the survival of PTC patients. The molecular mechanisms of DM in PTC have not been systematically studied. We performed whole exome sequencing and GeneseeqPrime (425 genes) panel sequencing of the primary tumor, plasma and matched white blood cell samples from 20 PTC with DM and 46 PTC without DM. We identified somatic mutations, gene fusions and copy number alterations and analyzed their relationships with DM of PTC. BRAF-V600E was identified in 73% of PTC, followed by RET fusions (14%) in a mutually exclusive manner (P < 0.0001). We found that gene fusions (RET, ALK or NTRK1) (P < 0.01) and chromosome 22q loss (P < 0.01) were independently associated with DM in both univariate and multivariate analyses. A nomogram model consisting of chromosome 22q loss, gene fusions and three clinical variables was built for predicting DM in PTC (C-index = 0.89). The plasma circulating tumor DNA (ctDNA) detection rate in PTC was only 38.9%; however, it was significantly associated with the metastatic status (P = 0.04), tumor size (P = 0.001) and invasiveness (P = 0.01). In conclusion, gene fusions and chromosome 22q loss were independently associated with DM in PTC and could serve as molecular biomarkers for predicting DM. The ctDNA detection rate was low in non-DM PTC but significantly higher in PTC with DM.

Neoadjuvant dose-modified docetaxel in squamous cell carcinoma of the head and neck: A phase 3 study.

OBJECTIVE: To evaluate the efficacy and safety of dose-modified docetaxel plus cisplatin and 5-fluorouracil (TPF) in Chinese patients with squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: This Phase III, open-label, multi-center study included Chinese adults with previously untreated TNM Stage III or IV SCCHN (NCT00995293). Patients were randomized (1:1) to induction chemotherapy with TPF (docetaxel 60 mg/m2 and cisplatin 60 mg/m2 on day 1 and 5-FU 750 mg/m2  per day continuous IV infusion on days 1-5) or PF (cisplatin 75 mg/m2 on day 1 and 5-FU 750 mg/m2  per day on days 1-5) every 3 weeks for 3-4 cycles. The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS in the TPF (n = 108) and PF (n = 111) groups was 400 days and 342 days (HR = 0.75; 95% CI, 0.53─1.06; p = .227), respectively. Overall response rate was higher for TPF versus PF (76.3% vs. 52.9%; p = .001), although this equalized following radiotherapy (75.0% vs. 73.9%). In the TPF and PF groups, ≥1 treatment-emergent adverse event was experienced by 104 (94.5%) and 110 (93.2%) patients, respectively. CONCLUSION: Adding dose-modified docetaxel to PF did not significantly improve PFS but may increase anti-tumor activity in Chinese patients with locally advanced SCCHN.

Diagnostic values of thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis diagnostic values of FNA-Tg.

Thyroglobulin measurement in the needle washout after fine-needle aspiration (FNA-Tg) served as an important measurement for suspicious recurrent or metastatic lesions. We conducted a pooled analysis to evaluate the diagnostic accuracy of FNA-Tg and searched electronic databases for original articles in English from 1993 through 2017. Finally, a total of 22 studies containing 2,670 lymph nodes (LNs) that enrolled participants with suspicious neck LNs during thyroid nodule workup or papillary thyroid cancer (PTC) follow-up were included. In our analysis, the overall pooled sensitivity for FNA-Tg was 0.91 (95%CI: 0.87-0.93), specificity was 0.94 (95% CI: 0.91-0.96). Meta regression revealed that the cutoff value and status of serum Tg were sources of heterogeneity for sensitivity, and the cutoff value was source of heterogeneity for specificity. Additionally, the cutoff value and status of serum Tg were sources of heterogeneity in the joint model. Subgroup analysis about cut-off value showed that the choice of 1 ng/mL had highest sensitivity, 40 ng/mL had highest specificity. At last, we arrived at the conclusion that FNA-Tg measurement had high specificity and sensitivity in the early detection of LNs metastases from PTC by our meta-analysis. The technique was simple and could be recommended to apply in any FNA facility, especially when LN were small-sized. Significantly, a better standardization of criteria for FNA-Tg detection and cutoff value was required to provide useful data and to improve management of PTC patients in the future.

Incidence and mortality of thyroid cancer in China, 2008-2012.

OBJECTIVE: To analyze the incidence and mortality rates of thyroid cancer (TC) in China from 2008 to 2012. METHODS: Incident and death cases of TC were retrieved from the National Central Cancer Registry (NCCR) database collecting from 135 cancer registries in China during 2008-2012. The crude incidence and mortality rates of TC were calculated by area (urban/rural), region (eastern, middle, western), gender and age group (0, 1-4, 5-9, …, 85+). China census in 2000 and world Segi's population were applied for age-standardized rates. Joinpoint (Version 4.6.0.0) model was used for time-trend analysis. RESULTS: The crude incidence rate of TC was 7.56/100,000 which ranked the seventh in overall cancers. The age-standardized incidence rates by China population (ASIRC) and by World population (ASIRW) were 6.25/100,000 and 5.52/100,000, respectively. The crude mortality of TC in China was 0.52/100,000. The age-standardized mortality rates by Chinese standard population (ASMRC) and by world standard population (ASMRW) were 0.34/100,000 and 0.32/100,000, respectively. Incidence and mortality rates of TC were higher in females than in males and higher in urban areas than in rural areas. Eastern areas had the highest incidence followed by middle and western areas. TC incidence increased dramatically after age of 15 years, then peaked at 14.08/100,000 in the group of 50-54 years and finally decreased sharply after 55 years old. TC mortality increased with age in population, reaching the peak of 5.09/100,000 in sub-population aged 85 years or older. TC incidence increased by 4.73 times from 2.40/100,000 in 2003 to 13.75/100,000 in 2012 with an average annual increase of 20%, while TC mortality only increased slightly around 0.32/100,000 from 0.26/100,000 to 0.36/100,000. CONCLUSIONS: Appropriate targeted prevention, early detection and treatment programs can be carried out to curb the rapid growth trend of TC and control the disease burden.

Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, we know little of mutational spectrum in the Chinese population. Thus, here we report the identification of somatic mutations for Chinese PTC using 402 tumor-normal pairs (Discovery: 91 pairs via exome sequencing; validation: 311 pairs via Sanger sequencing). We observed three distinct mutational signatures, evidently different from the two mutational signatures among Caucasian PTCs. Ten significantly mutated genes were identified, most previously uncharacterized. Notably, we found that long non-coding RNA (lncRNA) GAS8-AS1 is the secondary most frequently altered gene and acts as a novel tumor suppressor in PTC. As a mutation hotspot, the c.713A>G/714T>C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease (P = 0.009). Interestingly, the wild-type lncRNA GAS8-AS1 (A713T714) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G713C714). Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T>G (p.Ile291Ser) mutation in PTC malignant transformation. The BRAF c.1799T>A (p.Val600Glu) substitution was present in 59.0% Chinese PTCs, more frequently observed in patients with lymph node metastasis (P = 1.6 × 10(-4)). Together our study defines a exome mutational spectrum of PTC in the Chinese population and highlights lncRNA GAS8-AS1 and LPAR4 as potential diagnostics and therapeutic targets.

The Landscape of Circular RNA Expression Profiles in Papillary Thyroid Carcinoma Based on RNA Sequencing.

BACKGROUND/AIMS: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. However, the molecular mechanisms responsible for its tumorigenesis and progression remain largely unknown. Circular RNA (circRNA) is a novel type of noncoding RNA that can serve as an ideal biomarker due to its stability. Recent evidence suggests that circRNAs play important roles in tumorigenesis. This study aims to investigate circRNA expression profiles and their potential biological functions in PTC. METHODS: High-throughput RNA sequencing was used to assess circRNA expression profiles in PTC, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate dysregulated circRNAs. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic value of circRNAs for PTC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed circRNAs. Bioinformatic analyses were applied to predict interactions between circRNAs and microRNAs (miRNAs), and a circRNA-miRNA-mRNA network was constructed using Cytoscape software. RESULTS: We identified a number of differentially expressed circRNAs in PTC tissues compared with paired normal thyroid tissues, with chr5: 160757890-160763776-, chr12: 40696591-40697936+, chr7: 22330794-22357656-, and chr21: 16386665-16415895- being upregulated, and chr7: 91924203-91957214+, chr2: 179514891-179516047-, chr9: 16435553-16437522-, and chr22: 36006931-36007153- being downregulated. These findings were confirmed by qRT-PCR, and ROC curves indicated that they can serve as potential biomarkers for PTC. GO and KEGG pathway analyses showed that some of these circRNAs are related to cancers. Additionally, bioinformatic analyses revealed a potential competing-endogenous-RNA-regulating network among circRNAs, miRNAs, and mRNAs. CONCLUSIONS: Our study results depict the landscape of circRNA expression profiles in PTC and also provide potential biomarkers for PTC. Further functional and mechanistic studies of these circRNAs may improve our understanding of PTC tumorigenesis.