PRECISION: the Belgian molecular profiling program of metastatic cancer for clinical decision and treatment assignment.

PRECISION is an initiative from the Belgian Society of Medical Oncology (BSMO) in collaboration with several stakeholders, encompassing four programs that aim to boost genomic and clinical knowledge with the ultimate goal to offer patients with metastatic solid tumors molecularly guided treatments. The PRECISION 1 study has led to the creation of a clinico-genomic database. The Belgian Approach for Local Laboratory Extensive Tumor Testing (BALLETT) and GeNeo studies will increase the number of patients with advanced cancer that have comprehensive genotyping of their cancer.

Precision cancer medicine: What has translated into clinical use in Belgium?

Rationale: In 2016, Belgium launched the Next Generation Sequencing (NGS) Roadbook, consisting in 10 Actions, across the health care system, to facilitate the uptake of NGS in routine clinical practice. We compiled feedback on deployment of the NGS Roadbook from governmental stakeholders and beneficiaries: health policy makers, insurance providers, pathologists, geneticists, and oncologists.

Main Findings: The Roadbook ensured the establishment of a Commission on Personalized Medicine and NGS testing guidelines.

NGS for (Hemato-) Oncology in Belgium: Evaluation of Laboratory Performance and Feasibility of a National External Quality Assessment Program.

Next-generation sequencing (NGS) is being integrated into routine clinical practice in the field of (hemato-) oncology to search for variants with diagnostic, prognostic, or therapeutic value at potentially low allelic frequencies. The complex sequencing workflows used require careful validation and continuous quality control. Participation in external quality assessments (EQA) helps laboratories evaluate their performance and guarantee the validity of tests results with the ultimate goal of ensuring high-quality patient care.

Standardization of Somatic Variant Classifications in Solid and Haematological Tumours by a Two-Level Approach of Biological and Clinical Classes: An Initiative of the Belgian ComPerMed Expert Panel.

In most diagnostic laboratories, targeted next-generation sequencing (NGS) is currently the default assay for the detection of somatic variants in solid as well as haematological tumours. Independent of the method, the final outcome is a list of variants that differ from the human genome reference sequence of which some may relate to the establishment of the tumour in the patient. A critical point towards a uniform patient management is the assignment of the biological contribution of each variant to the malignancy and its subsequent clinical impact in a specific malignancy.

Roadbook for the implementation of next-generation sequencing in clinical practice in oncology and hemato-oncology in Belgium.

In the field of oncology research, next-generation sequencing has contributed significantly to the discovery of DNA mutations associated with diagnosis and prognosis. It also aids in the development of targeted therapies to specific mutations and the rise of personalized medicine. As part of molecular diagnostics in cancer patients, analysis by next-generation sequencing is becoming part of routine clinical practice.

microRNA expression in autonomous thyroid adenomas: Correlation with mRNA regulation.

The objective of the study was to identify the deregulated miRNA in autonomous adenoma and to correlate the data with mRNA regulation. Seven autonomous adenoma with adjacent healthy thyroid tissues were investigated. Twelve miRNAs were downregulated and one was upregulated in the tumors.

MiRNA expression may account for chronic but not for acute regulation of mRNA expression in human thyroid tumor models.

Background: For thyroid tumorigenesis, two main human in vitro models are available: primary cultures of human thyrocytes treated with TSH or EGF/serum as models for autonomous adenomas (AA) or papillary thyroid carcinomas (PTC) respectively, and human thyroid tumor derived cell lines. Previous works of our group have assessed properties of those models, with a special emphasis on mRNA regulations. It is often assumed that miRNA may be one of the primary events inducing these mRNA regulations.

miRNA expression in anaplastic thyroid carcinomas.

Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents an end stage of thyroid tumor progression. No effective treatment exists so far. In this study, we analyzed the miRNA expression profiles of 11 ATC by microarrays and their relationship with the mRNA expression profiles of the same 11 ATC samples.

Hyperosmotic stress induces cell cycle arrest in retinal pigmented epithelial cells.

Osmotic changes occur in many tissues and profoundly influence cell function. Herein, we investigated the effect of hyperosmotic stress on retinal pigmented epithelial (RPE) cells using a microarray approach. Upon 4-h exposure to 100 mM NaCl or 200 mM sucrose, 79 genes were downregulated and 72 upregulated.

5-aza-2'-deoxycytidine has minor effects on differentiation in human thyroid cancer cell lines, but modulates genes that are involved in adaptation in vitro.

Background: In thyroid cancer, the lack of response to specific treatment, for example, radioactive iodine, can be caused by a loss of differentiation characteristics of tumor cells. It is hypothesized that this loss is due to epigenetic modifications. Therefore, drugs releasing epigenetic repression have been proposed to reverse this silencing.

Thyroid cancer cell lines: an overview.

Human thyroid cancer cell lines are the most used models for thyroid cancer studies. They must be used with detailed knowledge of their characteristics. These in vitro cell lines originate from differentiated and dedifferentiated in vivo human thyroid tumors.

A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic.

Differentiation is central to development, while dedifferentiation is central to cancer progression. Hence, a quantitative assessment of differentiation would be most useful. We propose an unbiased method to derive organ-specific differentiation indices from gene expression data and demonstrate its usefulness in thyroid cancer diagnosis.

Role of Epac and protein kinase A in thyrotropin-induced gene expression in primary thyrocytes.

cAMP pathway activation by thyrotropin (TSH) induces differentiation and gene expression in thyrocytes. We investigated which partners of the cAMP cascade regulate gene expression modulations: protein kinase A and/or the exchange proteins directly activated by cAMP (Epac). Human primary cultured thyrocytes were analysed by microarrays after treatment with the adenylate cyclase activator forskolin, the protein kinase A (PKA) activator 6-MB-cAMP and the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (007) alone or combined with 6-MB-cAMP.

Metabolic reprogramming of the tumor.

Cancer is classically considered as a genetic and, more recently, epigenetic multistep disease. Despite seminal studies in the 1920s by Warburg showing a characteristic metabolic pattern for tumors, cancer bioenergetics has often been relegated to the backwaters of cancer biology. This review aims to provide a historical account on cancer metabolism research, and to try to integrate and systematize the metabolic strategies in which cancer cells engage to overcome selective pressures during their inception and evolution.

Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations.

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

Extracellular superoxide dismutase is a thyroid differentiation marker down-regulated in cancer.

Reactive oxygen species, specifically hydrogen peroxide (H(2)O(2)), have a significant role in hormone production in thyroid tissue. Although recent studies have demonstrated that dual oxidases are responsible for the H(2)O(2) synthesis needed in thyroid hormone production, our data suggest a pivotal role for superoxide dismutase 3 (SOD3) as a major H(2)O(2)-producing enzyme. According to our results, Sod3 is highly expressed in normal thyroid, and becomes even more abundant in rat goiter models.

Thyroid gene expression in familial nonautoimmune hyperthyroidism shows common characteristics with hyperfunctioning autonomous adenomas.

Context: Dominant activating mutations of the TSH receptor are the cause of familial nonautoimmune hyperthyroidism (FNAH) (inherited mutations affecting the whole gland since embryogenesis) and the majority of hyperfunctioning autonomous adenomas (AAs) (somatic mutations affecting only one cell later in the adulthood).

Objective: The objective of the study was defining the functional and molecular phenotypes of FNAH and comparing them with the ones of AA.

Design: Functional phenotypes were determined in vitro and molecular phenotypes by hybridization on microarray slides.

Human cancer cell lines: Experimental models for cancer cells in situ? For cancer stem cells?

Established human cancer cell lines are routinely used as experimental models for human cancers. Their validity for such use is analyzed and discussed, with particular focus on thyroid tumors. Although cell lines retain some properties of the cells of origin, from the points of view of their genetics, epigenetics and gene expression, they show clear differences in these properties compared to in vivo tumors.

Long-term EGF/serum-treated human thyrocytes mimic papillary thyroid carcinomas with regard to gene expression.

Constitutive activation of the RAS/RAF/MAPK pathway has been found in different tumor types including papillary thyroid carcinomas (PTCs). To get more insight into genes primarily regulated in the human tumor cells, an in vitro model was developed in which primary cultures of human thyrocytes were treated for different times with epidermal growth factor and serum (EGF/serum), which stimulate the MAPK cascade. Gene expression profiles were obtained by microarrays and compared to the expression profiles of PTCs.

ACLAME: a CLAssification of Mobile genetic Elements.

The ACLAME database (http://aclame.ulb.ac.

[Multicenter Belgian study of the results of total arthroplasty for persistent congenital hip dislocation].

The SO.B.C.

The osteoinductive capacity of differently HCl-decalcified bone alloimplants.

Three procedures to obtain bone inductive implants were tested heterotopically in 3-month-old allogeneic rats: 1) antigen-extracted HCl-decalcified at 4 degrees C, autolysed implant (AAA bone); 2) HCl-decalcified implant at 4 degrees C; 3) HCl-decalcified implant at room temperature. Each type of implant was either deep-frozen at -35 degrees C for at least 2 months or immediately freeze-dried. The bone inductive capacity of the differently HCl-decalcified cortical bone implant was evaluated at 2 months by isotopic strontium incorporation and by ash-weight measurements.