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Researchers ID Genes, Signaling Pathways Implicated in Sarcoma Subtypes

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A team of researchers led by Memorial Sloan-Kettering Cancer Center in New York has analyzed a combination of DNA sequence, copy number, and mRNA expression to identify several genes associated with soft-tissue sarcoma subtypes — the first large-scale study of genomic alterations in this type of cancer, according to the investigators.

The team, led by Samuel Singer at Sloan-Kettering and Matthew Meyerson at the Dana-Farber Cancer Institute and the Broad Institute, performed their analysis on 207 samples of soft-tissue sarcoma encompassing seven major subtypes. They initially analyzed tumor and matched normal DNA from 47 samples encompassing six subtypes, and they sequenced 722 protein-coding and microRNA genes, verifying discovered mutations with mass spectrometry-based genotyping.

Their results, published in the advance online edition of Nature Genetics this past weekend, found 28 somatic nonsynonymous coding point mutations and nine somatic insertions and deletions involving 21 genes in total. They did not detect any mutations in microRNA genes. The researchers then extended the analysis to an additional 160 tumors, for which they genotyped mutation sites identified in the initial sequencing study and resequenced exons of NF1 and ERBB4 in pleomorphic liposarcoma and myxofibrosarcoma, PIK3CA and KIT in myxoid/round-cell liposarcomas (MRCs), and CDH1 in dedifferentiated liposarcoma.

According to their findings, KIT was frequently mutated in gastrointestinal stromal tumors (GISTs), and in one MRC sample. In addition, mutated PIK3CA was found in 18 percent of MRCs, TP53 in 17 percent of pleomorphic liposarcomas, and NF1 in 10.5 percent of myxofibrosarcomas and 8 percent of pleomorphic liposarcoma. In particular, the researchers noted that they uncovered diverse alterations of NF1 in several sarcoma subtypes, and said that their findings complement recent reports of NF1 alterations in lung cancers and glioblastomas.

In addition, the researchers found that short hairpin RNA-based knockdown of several genes amplified in dedifferentiated liposarcoma, including CDK4 and YEATS4, decreased cell proliferation.

"Our findings lend additional support to the idea that YEATS4 is probably a key amplified gene in cancer, as recently suggested through a weight-of-evidence classification scheme proposed for identifying such amplified cancer genes," the researchers wrote.

"This data set provides the most comprehensive database of sarcoma genome alterations to date, revealing genes and signaling pathways not previously associated with this group of diseases," they added. "This study provides evidence for the therapeutic importance of genomic alterations in sarcoma; the results should encourage pursuit of next-generation sequencing strategies that will continue to define the landscape of genomic aberrations in these deadly diseases."

Data from the study is available from the MSKCC Cancer Genomics Data Portal.

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