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

ABSTRACT: 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% of pleomorphic liposarcomas) and PIK3CA (18% of myxoid/round-cell liposarcomas, or MRCs). PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes. In myxofibrosarcomas and pleomorphic liposarcomas, we found both point mutations and genomic deletions affecting the tumor suppressor NF1. Finally, we found that short hairpin RNA (shRNA)-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation. Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy.

SUBMITTER: Barretina J

PROVIDER: S-EPMC2911503 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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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 sarcoma (STS) represent a rare tumor entity, accounting for less than 1% of adult malignancies. The cornerstone of curative intent treatment is surgery with free margins, although the extent of the surgical approach has been subject to change in the last decades. Multimodal approaches usually including radiation therapy have replaced extensive surgical procedures in order to preserve functionality while maintaining adequate local control. However, the possibility to apply adequate radiation doses by external beam radiation therapy (EBRT) can be limited in some situation especially in case of directly adjacent organs at risk with low radiation tolerance. Application of at least a part of the total dose via intraoperative radiation therapy (IORT) with a single fraction during the surgical procedure may overcome those limitations, because radiosensitive structures can be moved out of the radiation field resulting in reduced toxicity while the enhanced biological effectivity of the high single dose improves local control. The current review summarizes rationale, techniques, oncological and functional outcomes including possible pitfalls and associated toxicities based on the published literature for IORT focusing on extremity and retroperitoneal STS. In extremity STS, combination of limb-sparing surgery, IORT and pre- or postoperative EBRT with moderate doses consistently achieved excellent local control rates at least comparable to approaches using EBRT alone but usually including patient cohorts with higher proportions of unfavourable prognostic factors. Further on, IORT containing approaches resulted in very high limb preservation rates and good functional outcome, probably related to the smaller high dose volume. In retroperitoneal STS, the combination of preoperative EBRT, surgery and IORT consistently achieved high local control rates which seem superior to surgery alone or surgery with EBRT at least with regard to local control and in some reports even to overall survival. Further on, preoperative EBRT in combination with IORT seems to be superior to the opposite combination with regard to local control and toxicity. No major differences in wound healing disturbances or postoperative complication rates can be observed with IORT compared to non-IORT containing approaches. Neuropathy of major nerves remains a dose limiting toxicity requiring dose restrictions or exclusion from target volume. Gastrointestinal structures and ureters should be excluded from the IORT area whenever possible and the IORT volume should be restricted to the available minimum. Nevertheless, IORT represents an ideal boosting method if combined with EBRT and properly executed by experiences users which should be further evaluated preferably in prospective randomized trials.

Dataset Information

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

Publications

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

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