Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer.

Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAFV600E and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.

Interaction of BRAF-induced ETS factors with mutant TERT promoter in papillary thyroid cancer.

Synergistic effects of BRAFV600E and TERT promoter mutations on the poor clinical outcomes in papillary thyroid cancer (PTC) have been demonstrated. The potential mechanism of this phenomenon has been proposed: MAPK pathway activation by the BRAFV600E mutation may upregulate E-twenty six (ETS) transcription factors, increasing TERT expression by binding to the ETS-binding site generated by the TERT promoter mutation; however, it has not yet been fully proven. This article provides transcriptomic insights into the interaction between BRAFV600E and TERT promoter mutations mediated by ETS factors in PTC. RNA sequencing data on 266 PTCs from The Cancer Genome Atlas and 65 PTCs from our institute were analyzed for gene expression changes and related molecular pathways, and the results of transcriptomic analyses were validated by in vitro experiments. TERT mRNA expression was increased by the coexistence of BRAFV600E and TERT promoter mutations (fold change, 16.17; q-value = 7.35 × 10-12 vs no mutation). In the ETS family of transcription factors, ETV1, ETV4 and ETV5 were upregulated by the BRAFV600E/MAPK pathway activation. These BRAFV600E-induced ETS factors selectively bound to the mutant TERT promoter. The molecular pathways activated by BRAFV600E were further augmented by adding the TERT promoter mutation, and the pathways related to immune responses or adhesion molecules were upregulated by TERT expression. The mechanism of the synergistic effect between BRAFV600E and TERT promoter mutations on cancer invasiveness and progression in PTC may be explained by increased TERT expression, which may result from the BRAF-induced upregulation of several ETS transcription factors.

Merkel cell carcinoma: our experience with seven patients in Korea and a literature review.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare but malignant cutaneous neuroendocrine carcinoma. As MCC has primarily been reported in Caucasians, MCC cases in Korea have not yet been reported. The purpose of this study was to retrospectively review our experience with the surgical treatment of MCC in Korea and to study its management and outcome. METHOD: We retrospectively reviewed seven MCC case files between 2000 and 2008 from a single institution. We analysed patient characteristics, tumour location and size, staging, treatment methods and outcomes. We performed polymerase chain reaction (PCR) to detect Merkel cell polyomavirus (MCPyV) from formalin-fixed paraffin-embedded tissue specimens. RESULTS: Two patients had stage I tumours, four patients had stage II tumours and one patient had a stage III tumour. Wide local excision with a clear resection margin was the primary modality of treatment in all cases. Adjuvant radiotherapy and chemotherapy were performed for selected patients. Recurrence was observed in two out of the seven cases during the follow-up period. MCPyV was detected by PCR in all seven cases. CONCLUSION: MCC is an aggressive skin cancer, and pathologic lymph node evaluation is important for staging. Wide excision is the primary modality of treatment, but adjuvant radiotherapy could be positively considered if the tumour is large and the lesion is not confined to the dermis. MCPyV was detected by PCR in all cases, which suggests that MCPyV is also a putative aetiological agent in the carcinogenesis of MCC in Korea.

Dynamic response of the transcriptome of a psychrophilic diatom, Chaetoceros neogracile, to high irradiance.

Large-scale RNA profiling revealed that high irradiance differentially regulated 577 out of 1,439 non-redundant genes of the Antarctic marine diatom Chaetoceros neogracile, represented on a custom cDNA chip, during 6 h of treatment. Among genes that were up- or down-regulated more than twofold within 30 min of treatment (310/1,439), about half displayed an acclimatory response during 6 h under high light. Expression of the remaining non-acclimatory genes also rapidly returned to initial levels within 30 min following a shift to low irradiance. High light altered expression of most of the photosynthesis genes (48/70), in contrast to genes in other functional categories. In addition, opposite response patterns were provoked in genes encoding fucoxanthin chlorophyll a/c binding protein (FCP), the main component of the diatom light-harvesting complex; high irradiance caused a decrease in expression of most FCP genes, but drove the rapid and specific up-regulation of ten others. C. neogracile responded very promptly to a change in light intensity by rapidly adjusting the transcript levels of FCP genes up-regulated by high light, and these dynamic adjustments coincided well with diatoxanthin (Dtx) levels formed by the xanthophyll cycle under the same conditions. The observation that the non-photochemical quenching (NPQ) capacity of this polar diatom was highly dependent on Dtx, which could bind to FCP and trigger NPQ, suggests that the up-regulated FCP gene products may participate in a photoprotective process as Dtx-binding proteins.

Transcriptome analysis of acclimatory responses to thermal stress in Antarctic algae.

A customized cDNA chip analysis provided the relative expression profiling of 1439 ESTs of Chaetoceros neogracile in culture environments maintained between 4 and 10 degrees C. Among the 1439 probes, 21.5% were differentially regulated (2-fold) by the temperature upshift within three days. Up-regulation was more prominent among cytoprotective genes, whereas down-regulation was featured in photosynthetic genes. A third of the differentially expressed genes had an unknown function or no similarity to known genes, highlighting their potential importance as a resource to identify key players in the acclimation response of polar algae under thermal stress. Our transcriptome analysis also revealed novel aspects of temperature-responsive, coordinated changes in the abundance of specific mRNAs, along with the rapid establishment of molecular homeostasis in polar algae. Unexpectedly, a small set of genes encoding fucoxanthin chlorophyll a/c-binding proteins were rapidly up-regulated by thermal stress, implying that they have different roles other than light harvesting.

Annotation and expression profile analysis of cDNas from the Antarctic diatom Chaetoceros neogracile.

To better understand the gene expression of the cold-adapted polar diatom, we conducted a survey of the Chaetoceros neogracile transcriptome by cDNA sequencing and expression of interested cDNAs from the Antarctic diatom. A non-normalized cDNA library was constructed from the C. neogracile, and a total of 2,500 cDNAs were sequenced to generate 1,881 high-quality expressed sequence tags (ESTs) (accession numbers EL620615-EL622495). Based on their clustering, we identified 154 unique clusters comprising 342 ESTs. The remaining 1,540 ESTs did not cluster. The number of unique genes identified in the data set is thus estimated to be 1,694. Taking advantage of various tools and databases, putative functions were assigned to 939 (55.4%) of these genes. Of the remaining 540 (31.9%) unknown sequences, 215 (12.7%) appeared to be C. neogracile-specific since they lacked any significant sequence similarity to any sequence available in the public databases. C. neogracile consisted of a relatively high percentage of genes involved in metabolism, genetic information processing, cellular processes, defense or stress resistance, photosynthesis, structure, and signal transduction. From the ESTs, the expression of these putative C. neogracile genes was investigated: fucoxanthin chlorophyll (chl) a,c-binding protein (FCP), ascorbate peroxidase (ASP), and heat-shock protein 90 (HSP90). The abundance of ASP and HSP90 changed substantially in response to different culture conditions, indicating the possible regulation of these genes in C. neogracile.