Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Whole-transcript expression data for soft-tissue sarcoma tumors and control normal fat specimens

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 specimens were profiled on Affymetrix U133A arrays per manufacturer's instructions.

ORGANISM(S): Homo sapiens

SUBMITTER: Barry Taylor

PROVIDER: E-GEOD-21122 | 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.

Dataset Information

Whole-transcript expression data for soft-tissue sarcoma tumors and control normal fat specimens

Publications

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

Similar Datasets

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