A framework for scientific advice on health: EuSANH's principles and guidelines.

BACKGROUND: Society expects politicians to make sound decisions by bringing the best evidence to bear on the health problems in question. Performing this task requires access to independent sources of sound scientific advice. The European Science Advisory Network for Health (EuSANH) is a network of national science advisory bodies in Europe which are active in the field of health and provide independent scientific advice to their authorities. The EuSANH addressed this question in a European project. METHODS: Guidelines and principles for producing sound advice have been formulated after international comparative evaluations and extensive discussions among participants of the EuSANH-ISA project with input from international experts. RESULTS: A framework for scientific advice on health has been produced. CONCLUSIONS: This framework will ensure a uniform approach and thus opens possibilities for collaboration between science advisory bodies.

The synovial-sarcoma-associated SS18-SSX2 fusion protein induces epigenetic gene (de)regulation.

Fusion of the SS18 and either one of the SSX genes is a hallmark of human synovial sarcoma. The SS18 and SSX genes encode nuclear proteins that exhibit opposite transcriptional activities. The SS18 protein functions as a transcriptional coactivator and is associated with the SWI/SNF complex, whereas the SSX proteins function as transcriptional corepressors and are associated with the polycomb complex. The domains involved in these opposite transcriptional activities are retained in the SS18-SSX fusion proteins. Here, we set out to determine the direct transcriptional consequences of conditional SS18-SSX2 fusion protein expression using complementary DNA microarray-based profiling. By doing so, we identified several clusters of SS18-SSX2-responsive genes, including a group of genes involved in cholesterol synthesis, which is a general characteristic of malignancy. In addition, we identified a group of SS18-SSX2-responsive genes known to be specifically deregulated in primary synovial sarcomas, including IGF2 and CD44. Furthermore, we observed an uncoupling of EGR1, JUNB, and WNT signaling in response to SS18-SSX2 expression, suggesting that the SWI/SNF-associated coactivation functions of the SS18 moiety are impaired. Finally, we found that SS18-SSX2 expression affects histone modifications in the CD44 and IGF2 promoters and DNA methylation levels in the IGF2 imprinting control region. Together, we conclude that the SS18-SSX2 fusion protein may act as a so-called transcriptional "activator-repressor," which induces downstream target gene deregulation through epigenetic mechanisms. Our results may have implications for both the development and clinical management of synovial sarcomas.

Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation.

Synovial sarcoma is an aggressive spindle cell sarcoma with two major histological subtypes, biphasic and monophasic, defined respectively by the presence or absence of areas of glandular epithelial differentiation. It is characterized by a specific chromosomal translocation, t(X;18)(p11.2;q11.2), which juxtaposes the SYT gene on chromosome 18 to either the SSX1 or the SSX2 gene on chromosome X. The chimeric SYT-SSX products are thought to function as transcriptional proteins that deregulate gene expression, thereby providing a putative oncogenic stimulus. We investigated the pattern of gene expression in synovial sarcoma using cDNA microarrays containing 6548 sequence-verified human cDNAs. A tissue microarray containing 37 synovial sarcoma samples verified to bear the SYT-SSX fusion was constructed for complementary analyses. Gene expression analyses were performed on individual tumor samples; 14 synovial sarcomas, 4 malignant fibrous histiocytomas, and 1 fibrosarcoma. Statistical analysis showed a distinct expression profile for the group of synovial sarcomas as compared to the other soft tissue sarcomas, which included variably high expression of ERBB2, IGFBP2, and IGF2 in the synovial sarcomas. Immunohistochemical analysis of protein expression in tissue microarrays of 37 synovial sarcomas demonstrated strong expression of ERBB2 and IGFBP2 in the glandular epithelial component of biphasic tumors and in solid epithelioid areas of some monophasic tumors. Fluorescence in situ hybridization analysis indicated that the ERBB2 overexpression was not because of gene amplification. Differentially expressed genes were also found in a comparison of the expression profiles of the biphasic and monophasic histological subgroups of synovial sarcoma, notably several keratin genes, and ELF3, an epithelial-specific transcription factor gene. Finally, we also noted differential overexpression of several neural- or neuroectodermal-associated genes in synovial sarcomas relative to the comparison sarcoma group, including OLFM1, TLE2, CNTNAP1, and DRPLA. Our high-throughput studies of gene expression patterns, complemented by tissue microarray studies, confirm the distinctive expression profile of synovial sarcoma, provide leads for the study of glandular morphogenesis in this tumor, and identify a new potential therapeutic target, ERBB2, in a subset of cases.

Chromosomal imbalances in diffuse large B-cell lymphoma detected by comparative genomic hybridization.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. In contrast to many other hematological malignancies, no chromosomal abnormalities with a diagnostic or prognostic value have been identified in DLBCL. Numerical chromosomal imbalances were characterized by comparative genomic hybridization (CGH) performed on 54 DLBCL tumors from a total of 40 patients. The clonal relatedness was demonstrated in 9 of 11 pairs of matched diagnostic tumors and their relapses as determined by IGH gene rearrangement analysis and/or the CGH profiles. Furthermore, immunohistochemical expression analyses of BCL2 and BCL6/LAZ3 were performed on all cases. Copy number changes were detected in 94% of the diagnostic tumor samples and in all of the relapses. Chromosomal losses in diagnostic tumors were preferentially observed at 8p22-pter (29%), 1p34-pter (26%), 6q23-qter (20%), 17p12-pter (17%) and 22q (17%), 9p23-pter (14%), whereas gains were mainly seen in Xq25-26 (43%), 13q22 (26%), 12cen-q14 (20%), 3q24-25 (11%), 7 (11%), and 18q12-21 (11%). Loss of 22q was significantly more commonly seen in the diagnostic tumor samples with more advanced clinical stage in other words, Stage III-IV compared with Stage I-II, and band 18q21 was significantly more often gained in relapses as compared to diagnostic tumors. None of the recurrent alterations were detected as a single abnormality, suggesting that other genetic lesions below the detection level of CGH may be the initiating event in the tumorigenesis of DLBCL. However, the distribution of CGH alterations support the idea of a progression of genetic events where loss of 8p and 9p and gain of 3q, 13q, and 18q would represent relatively early events because they were distributed in tumors with only two abnormalities.