Noninvasive near-infrared fluorescent protein-based imaging of tumor progression and metastases in deep organs and intraosseous tissues

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IDH mutation status in a series of 88 head and neck chondrosarcomas: different profile between tumors of the skull base and tumors involving the facial skeleton and the laryngotracheal tract

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Gene expression profiling of solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare spindle-cell tumors. Their cell-of-origin and molecular basis are poorly known. They raise several clinical problems. Differential diagnosis may be difficult, prognosis is poorly apprehended by histoclinical features, and no effective therapy exists for advanced stages.We profiled 16 SFT samples using whole-genome DNA microarrays and analyzed their expression profiles with publicly available profiles of 36 additional SFTs and 212 soft tissue sarcomas (STSs). Immunohistochemistry was applied to validate the expression of some discriminating genes.SFTs displayed whole-genome expression profiles more homogeneous and different from STSs, but closer to genetically-simple than genetically-complex STSs. The SFTs/STSs comparison identified a high percentage (∼30%) of genes as differentially expressed, most of them without any DNA copy number alteration. One of the genes most overexpressed in SFTs encoded the ALDH1 stem cell marker. Several upregulated genes and associated ontologies were also related to progenitor/stem cells. SFTs also overexpressed genes encoding therapeutic targets such as kinases (EGFR, ERBB2, FGFR1, JAK2), histone deacetylases, or retinoic acid receptors. Their overexpression was found in all SFTs, regardless the anatomical location. Finally, we identified a 31-gene signature associated with the mitotic count, containing many genes related to cell cycle/mitosis, including AURKA.We established a robust repertoire of genes differentially expressed in SFTs. Certain overexpressed genes could provide new diagnostic (ALDH1A1), prognostic (AURKA) and/or therapeutic targets

Comprehensive genome characterization of solitary fibrous tumors using high‐resolution array‐based comparative genomic hybridization

International audienceSolitary fibrous tumors (SFTs) are rare spindle cell tumors with limited therapeutic options. Their molecular basis is poorly known. No consistent cytogenetic abnormality has been reported. We used high-resolution whole-genome array-based comparative genomic hybridization (Agilent 244K oligonucleotide chips) to profile 47 samples, meningeal in >75% of cases. Few copy number aberrations (CNAs) were observed. Sixty-eight percent of samples did not show any gene CNA after exclusion of probes located in regions with referenced copy number variation (CNV). Only low-level CNAs were observed. The genomic profiles were very homogeneous among samples. No molecular class was revealed by clustering of DNA copy numbers. All cases displayed a "simplex" profile. No recurrent CNA was identified. Imbalances occurring in >20%, such as the gain of 8p11.23-11.22 region, contained known CNVs. The 13q14.11-13q31.1 region (lost in 4% of cases) was the largest altered region and contained the lowest percentage of genes with referenced CNVs. A total of 425 genes without CNV showed copy number transition in at least one sample, but only but only 1 in at least 10% of samples. The genomic profiles of meningeal and extra-meningeal cases did not show any differences

Microscopic aspects and ALDH1 expression using IHC.

<p><b><i>A.</i></b> Microscopic features (HES) of a glioblastoma used as positive control for ALDH1 immunostaining. <b><i>B.</i></b> ALDH1 expression in the cytoplasm of few astrocytic tumor cells. <b><i>C–D.</i></b> Microscopic features (HES) of an SFT in a collagenic area (C) and of an SFT in a cellular area with an “hemangiopericytoma” vascular pattern (D). <b><i>E–F.</i></b> ALDH1 immunostaining in a collagenic area (E) and in a cellular area (F): note the strong and diffuse expression in the cytoplasm of tumor cells. For all images, magnification is ×25.</p

Supervised analyses of SFTs based on the location and mitotic count.

<p><b><i>A.</i></b> Legend similar to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064497#pone-0064497-g002" target="_blank">Figure 2</a>, but applied to 16 SFT samples (12 meningeal M and 4 extra-meningeal Extra-M). The signature includes 573 genes. Samples are ordered from left to right according to the decreasing correlation coefficient of their expression profile with the mean profile of the meningeal samples. The solid vertical line indicates the threshold of 50% (equiprobability according to PAM model) that separates the two signature-predicted classes of samples. The genes are ordered form top to bottom according to their decreasing SAM statistics of meningeal SFT association. <b><i>B.</i></b> Similar to A, but applied to the 23 samples from the independent validation set (8 meningeal M and 15 extra-meningeal Extra-M). <b><i>C.</i></b> Similar to A, but applied to 16 SFT samples (10 with low mitotic count MC and 6 with high count). The signature includes 31 genes. Samples are ordered from left to right according to the decreasing metagene score. The solid vertical line indicates the optimal cut-point (0.33) defined using ROC analysis that separates the two signature-predicted classes of samples. <b><i>D.</i></b> Similar to C, but applied to the 13 samples from the independent validation set (all with low mitotic count).</p

Histoclinical characteristics of SFT samples.

<p>Histoclinical characteristics of SFT samples.</p

Supervised analysis of SFTs and all STSs.

<p><b><i>A.</i></b> Classification of 208 samples (29 SFTs and 179 STSs) from the learning set using the 3,401-gene expression signature. <i>Top</i>, matrix of gene expression data. The legend is similar to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064497#pone-0064497-g001" target="_blank">Figure 1A</a>. Tumor samples are ordered from left to right according to the decreasing correlation coefficient of their expression profile with the mean profile of the SFT samples. The genes are ordered form top to bottom according to their decreasing SAM statistics of SFT association. <i>Middle</i>: actual histological type (black, SFT; white STS). <i>Bottom,</i> probability (from 0 to 1) for each sample to be predicted as non-SFT by the PAM model based on the signature. Red dots represent SFT samples, and black STS samples. The solid orange vertical line indicates the threshold of 50% (equiprobability according to PAM model) that separates the two signature-predicted classes of samples. <b><i>B.</i></b> Similar to A, but applied to the 56 samples (23 SFTs and 33 STSs) from the independent validation set.</p

Whole-genome expression profiling of SFTs and STSs.

<p><b><b><i>A.</i></b></b> Hierarchical clustering of 208 samples (29 SFTs and 179 STSs) and 10,089 genes with significant variation in mRNA expression level across the samples (SD≥0.25). Each row of the data matrix represents a gene and each column a sample. Expression levels are depicted according to the color scale shown at the bottom, where red and green indicate expression levels respectively above and below the median and the color saturation represents the magnitude of deviation from the median. The dendrogram of samples (above matrixes) represents overall similarities in gene expression profiles and is zoomed in B. Colored bars to the right indicate the locations of 8 gene clusters of interest. <b><i>B.</i></b> Dendrogram of samples. <i>Top</i>, two large groups of samples (designated I and II) are evidenced by clustering and delimited by the orange vertical line. Each cluster is divided into two subclusters (a and b) delimited by orange dotted vertical lines. <i>Bottom</i>, some characteristics of samples are represented according to a color ladder: sample type (black, SFT; white, STS); histological subtype (black, SFT; pink, DFSP; salmon, GIST; dark blue, synovial sarcoma; light green, myxoid/round cells liposarcoma; yellow, dedifferentiated liposarcoma; dark green, pleomorphic liposarcoma; red, leiomyosarcoma; purple, malignant fibrous histiocytoma); degree of genetic complexity of STSs (white, simple; grey, complex). <b><i>C.</i></b> Metagene (MG) of the 8 gene clusters shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064497#pone-0064497-g001" target="_blank">Figure 1A</a> (the metagene is the mean expression level of included genes) and four control genes (EntrezGene symbol) known as differentially expressed according to the histological subtype.</p