Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Affymetrix SNP array data for soft tissue sarcoma samples

ABSTRACT: Soft tissue sarcomas are aggressive mesenchymal cancers that affect more than 10,600 new patients per year in the US, about 40% of whom will die of their disease. Soft tissue sarcomas exhibit remarkable histologic diversity, with more than 50 recognized subtypes, but our knowledge of their genomic alterations is limited. Here we describe the results of an integrative analysis of DNA sequence, copy number, and mRNA expression in 207 samples encompassing seven major subtypes. Genes mutated in more than 5% of samples within a subtype were KIT (in gastrointestinal stromal cell tumors, or GISTs), TP53 (pleomorphic liposarcomas), PIK3CA (myxoid/round-cell liposarcoma), and NF1 (both myxofibrosarcoma and pleomorphic liposarcoma). We show evidence that PIK3CA mutations, found in 18% of myxoid/round-cell liposarcomas, activate AKT in vivo and are associated with poor outcomes. Point mutations in the tumor suppressor gene NF1 were discovered in both myxofibrosarcomas and pleomorphic liposarcomas, while genomic deletions were observed in all subtypes at varying frequencies. Finally, we found that short hairpin RNA-based knockdown of a subset of genes that are amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields the most detailed map of molecular alterations across diverse sarcoma subtypes to date and provides potential subtype-specific targets for therapy. Human soft tissue sarcoma samples and their matched normal DNA were profiled on Affymetrix 250K SNP (Sty) arrays per manufacturer's instructions

ORGANISM(S): Homo sapiens

SUBMITTER: Barry Taylor

PROVIDER: E-GEOD-21123 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.

Barretina Jordi J Taylor Barry S BS Banerji Shantanu S Ramos Alexis H AH Lagos-Quintana Mariana M Decarolis Penelope L PL Shah Kinjal K Socci Nicholas D ND Weir Barbara A BA Ho Alan A Chiang Derek Y DY Reva Boris B Mermel Craig H CH Getz Gad G Antipin Yevgenyi Y Beroukhim Rameen R Major John E JE Hatton Charles C Nicoletti Richard R Hanna Megan M Sharpe Ted T Fennell Tim J TJ Cibulskis Kristian K Onofrio Robert C RC Saito Tsuyoshi T Shukla Neerav N Lau Christopher C Nelander Sven S Silver Serena J SJ Sougnez Carrie C Viale Agnes A Winckler Wendy W Maki Robert G RG Garraway Levi A LA Lash Alex A Greulich Heidi H Root David E DE Sellers William R WR Schwartz Gary K GK Antonescu Cristina R CR Lander Eric S ES Varmus Harold E HE Ladanyi Marc M Sander Chris C Meyerson Matthew M Singer Samuel S

Nature genetics 20100704 8

Soft-tissue sarcomas, which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States, show remarkable histologic diversity, with more than 50 recognized subtypes. However, knowledge of their genomic alterations is limited. We describe an integrative analysis of DNA sequence, copy number and mRNA expression in 207 samples encompassing seven major subtypes. Frequently mutated genes included TP53 (17% of pleomorphic liposarcomas), NF1 (10.5% of myxofibrosarcomas and 8 ...[more]

PMID: 20601955

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Project description:Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25-30% response rate in large multi-institutional trials. Although liposarcomas are the most common histological form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that utilizes Alternative Lengthening of Telomeres (ALT) mechanism of telomere maintenance, which may be particularly important in modulating the response of this tumor type to DNA damaging agents. We present detailed baseline molecular and genomic data, including genome wide copy number and transcriptome profiles, for this model compared to its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also demonstrate the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provide a powerful new tool to develop treatments for this clinically poorly-tractable tumor, and to investigate the contribution that ALT makes to modulating sensitivity to DNA damaging chemotherapeutic agents such as doxorubicin. Affymetrix U133 2.0 expression analyses were performed for 30 liposarcoma tumors, including 2 recurrences of 2 tumors. In addition, analyses were performed for three replicates of a tumor-derived cell line, LS2, as well as the tumor from which it was derived (5228). Finally, the Affymetrix Human Genome 50K DNA Mapping Array was used to determine copy number profiles for two Passages of LS2, as well as tumor 5228.

Project description:Liposarcomas are rare, heterogeneous and malignant tumors that can be divided into five histological subtypes with different characteristics and clinical behavior. Treatment consists of surgery in combination with systemic chemotherapy, but nevertheless mortality rates are high. More insight into the biology of liposarcoma tumorigenesis is needed to devise novel therapeutic approaches. MicroRNAs (miRNAs) have been associated with carcinogenesis in many tumors and may function as tumor suppressor or oncogene. In this study we examined miRNA expression in an initial series of 57 human liposarcomas (including all subtypes), lipomas and normal fat by miRNA microarrays. Supervised hierarchical clustering of the most differentially expressed miRNAs (p<0.0002) distinguished most liposarcoma subtypes and control tissues. The distinction between well differentiated liposarcomas and benign lipomas was blurred, suggesting these tumor types may represent a biological continuum. MiRNA signatures of liposarcoma subtypes were established and validated in an independent series of 58 liposarcomas and control tissues. The expression of the miR-143/145 and miR-144/451 cluster members was clearly reduced in liposarcomas compared to normal fat. Overexpression of miR-145 and miR-451 in liposarcoma cell lines decreased cellular proliferation rate, impaired cell cycle progression and induced apoptosis. In conclusion, we show that miRNA expression profiling can be used to discriminate liposarcoma subtypes, which could aid in objective diagnostic decision making. In addition, our data indicate that miR-145 and miR-451 act as tumor suppressors in adipose tissue and show that re-expression of these miRNAs could be a promising therapeutic strategy for liposarcomas. 57 samples discovery set, 58 samples in validation set, subdivided in 5 liposarcoma subtypes plus lipomas and normal fat as control samples. Each sample was analysed on one array. All array probes are present in duplicate.

Dataset Information

Affymetrix SNP array data for soft tissue sarcoma samples

Publications

Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy.

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