Project description:This SuperSeries is composed of the following subset Series: GSE12439: Genomic profiling of chondrosarcoma: implications for the distinction between central and peripheral tumors GSE12475: Genomic profiling of chondrosarcoma: implications for the distinction between central and peripheral tumors Refer to individual Series
Project description:DNA copy number analysis of 67 fresh frozen chondrosarcoma biopsies using 32k BAC and 244k oligo array CGH. Genomic imbalances, in most tumors affecting large regions of the genome, were found in 90% of the cases. Although rare, recurrent amplifications were found at 8q24.21-q24.22 and 11q22.1-q22.3, and homozygous deletions of loci previously implicated in chondrosarcoma development affected the CDKN2A, EXT1 and EXT2 genes. Keywords: chondrosarcoma, array comparative genomic hybridization
Project description:DNA methylation and copy number variation (CNV) profiling has emerged as a promising tool for the classification of bone and soft tissue tumors. We evaluated its utility in cartilage tumors, where distinguishing low-grade from high-grade conventional central chondrosarcoma (CS) as well as atypical cartilaginous tumors (ACT) from enchondromas are frequent diagnostic challenges, particularly on biopsy material. We analyzed 214 chondrogenic tumors, including enchondromas, ACT, conventional central, dedifferentiated, and clear cell chondrosarcomas, and determined their IDH1/2 mutation status. Unsupervised dimensionality reduction of genome-wide DNA methylation patterns revealed four clusters among IDH-mutant tumors (IDH-MUT-1: mostly enchondromas and ACT and some high-grade CS; IDH-MUT-2: predominantly high-grade CS; IDH-MUT-3: largely dedifferentiated CS; IDH-MUT-HN: distinct head and neck group with markedly different methylation pattern) and two clusters among IDH-wildtype tumors (IDH-WT-1 and IDH-WT-2: both primarily high-grade CS, with IDH-WT-2 showing higher tumor grade and more extensive CNVs). Clear cell chondrosarcomas formed a separate cluster (CC). The amount of CNVs, including loss of CDKN2A, increased with tumor grade, reflecting increased genomic instability during chondrosarcoma progression. Supervised classifiers trained separately, both on methylation and CNV data, distinguished low- and high-grade cartilaginous tumors with AUC values of 0.87–0.97 and 85–90% accuracy. Furthermore, we tested whether dedifferentiated chondrosarcoma (DDCS) can be distinguished from metastatic carcinomas and other high-grade sarcomas of bone. Across 246 reference samples, a supervised classifier achieved 97.2% accuracy (AUC 99.8%) and correctly identified 30/32 (93.8%) DDCS. These results indicate that DNA methylation and CNV data analysis provide a valuable tool for distinguishing most low- and high-grade chondrosarcomas, with additional utility also in differentiating DDCS from morphologic mimics.
Project description:Gene expression profiling of 17 fresh frozen chondrosarcoma biopsies using the Human-6 v2 Expression BeadChip (Illumina Inc., San Diego, CA, USA). DNA copy number analyses was also performed in these tumors. Keywords: chondrosarcoma, gene expression profiling, Illumina
Project description:Accurate staging of colorectal cancer (CRC) with clinicopathological parameters is important for predicting prognosis and guiding treatment but provides us no information about organ site of metastases. Patterns of genomic aberrations in primary colorectal tumors may reveal a chromosomal signature for organ specific metastases.
Project description:Chondrosarcomas represent the second most common primary bone malignancy. Despite the vulnerability of chondrosarcoma cells to nicotinamide adenine dinucleotide (NAD+) depletion, targeting the NAD+ synthesis pathway remains challenging due to broad implications in biological processes. Here, we establish SIRT1 as a central mediator reinforcing the dependency of chondrosarcoma cells on NAD+ metabolism via HIF-2α-mediated transcriptional reprogramming. SIRT1 knockdown abolishes aggressive phenotypes of chondrosarcomas in orthotopically transplanted tumors in mice. Chondrosarcoma cells thrive under glucose starvation by accumulating NAD+ and subsequently activating the SIRT1–HIF-2α axis. Decoupling this link via SIRT1 inhibition unleashes apoptosis and suppresses tumor progression in conjunction with chemotherapy. Unsupervised clustering analysis identifies a high-risk chondrosarcoma patient subgroup characterized by the upregulation of NAD+ biosynthesis genes. Finally, SIRT1 inhibition abolishes HIF-2α transcriptional activity and sensitizes chondrosarcoma cells to doxorubicin-induced cytotoxicity, irrespective of underlying pathways to accumulate intracellular NAD+. We provide system-level guidelines to develop therapeutic strategies for chondrosarcomas.
