Somatic Mutations Implicated in Progression from Well-Differentiated to Dedifferentiated Liposarcoma: An Exome Sequencing Approach
Andrew E Horvai, Kuang-Yu Jen. UCSF, San Francisco, CA
Background: The well-differentiated/dedifferentiated liposarcoma family represents the most common subtype of liposarcoma. Well-differentiated (WL) and dedifferentiated liposarcomas (DL) demonstrate amplification of chromosome subregion 12q13-q15. Preliminary data on a few liposarcoma cases have uncovered point mutations in specific genes (HDCA1, PTPN9 and DAZAP2) when compared to normal tissue. However, the specific genetic changes that distinguish between WL and DL, which may provide insights into tumor progression, are poorly understood. Upregulation of the MAPK-AP1 signaling axis has been proposed, but the mechanism is not known. The presence of discrete lipogenic and non-lipogenic components in DL provides a unique model system to investigate mechanisms of progression. Using high throughput exome sequencing we delineated the mutations that are unique to only the nonlipogenic components of DL, but are not present in matched lipogenic components.
Design: Two DL, with confirmed 12q13-15 amplification, were selected from departmental archives. Matched normal tissue, lipogenic and nonlipogenic (“dedifferentiated”) areas were separately dissected from formalin-fixed, paraffin embedded (FFPE) tissue. Each component was analyzed by whole exome sequencing using the Illumina platform achieving 86-fold average coverage. The data were filtered for known SNPs and analyzed for nonsynonymous somatic mutations and small insertions and deletions (indels).
Results: Fifty-seven genes were identified with point mutations that were present in nonlipogenic components of both DL but not in either matched lipogenic component or normal tissue. The presumed functions of mutated genes include signal transduction (RASSF1), tyrosine kinase receptor (FLT4), cell cycle control (UBXN11) and fatty acid metabolism (ACOX1). Mutations in the MAPK or AP1 families of genes were not observed. Indels of 30 and 33 genes, respectively, were identified in the nonlipogenic components, but none were common to both tumors.
Conclusions: Whole exome sequencing from FFPE tissue is a useful tool in the discovery phase to identify genes that drive tumorigenesis and progression. This study identifies novel somatic mutations in DL, a subset of which are specific to the nonlipogenic component. That many such mutations affect genes involved in cell proliferation suggests oncogenic potential in DL and are good candidates for further study.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 227, Tuesday Morning