Analysis of Multiple Sarcoma Expression Datasets: Implications for Classification, Oncogenic Pathway Activation and Chemotherapy ResistanceReport as inadecuate




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Background

Diagnosis of soft tissue sarcomas STS is challenging. Many remain unclassified not-otherwise-specified, NOS or grouped in controversial categories such as malignant fibrous histiocytoma MFH, with unclear therapeutic value. We analyzed several independent microarray datasets, to identify a predictor, use it to classify unclassifiable sarcomas, and assess oncogenic pathway activation and chemotherapy response.

Methodology-Principal Findings

We analyzed 5 independent datasets 325 tumor arrays. We developed and validated a predictor, which was used to reclassify MFH and NOS sarcomas. The molecular -match- between MFH and their predicted subtypes was assessed using genome-wide hierarchical clustering and Subclass-Mapping. Findings were validated in 15 paraffin samples profiled on the DASL platform. Bayesian models of oncogenic pathway activation and chemotherapy response were applied to individual STS samples. A 170-gene predictor was developed and independently validated 80-85% accuracy in all datasets. Most MFH and NOS tumors were reclassified as leiomyosarcomas, liposarcomas and fibrosarcomas. -Molecular match- between MFH and their predicted STS subtypes was confirmed both within and across datasets. This classification revealed previously unrecognized tissue differentiation lines adipocyte, fibroblastic, smooth-muscle and was reproduced in paraffin specimens. Different sarcoma subtypes demonstrated distinct oncogenic pathway activation patterns, and reclassified MFH tumors shared oncogenic pathway activation patterns with their predicted subtypes. These patterns were associated with predicted resistance to chemotherapeutic agents commonly used in sarcomas.

Conclusions-Significance

STS profiling can aid in diagnosis through a predictor tracking distinct tissue differentiation in unclassified tumors, and in therapeutic management via oncogenic pathway activation and chemotherapy response assessment.



Author: Panagiotis A. Konstantinopoulos , Elena Fountzilas , Jeffrey D. Goldsmith, Manoj Bhasin, Kamana Pillay, Nancy Francoeur, Towia A.

Source: http://plos.srce.hr/



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