Published online before print February 29, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070284

Article

A Developmental Model of Sarcomagenesis Defines a Differentiation-Based Classification for Liposarcomas

Igor Matushansky^*, Eva Hernando, Nicholas D. Socci, Tulio Matos, Joslyn Mills, Mark A. Edgar, Gary K. Schwartz^**, Samuel Singer^¶, Carlos Cordon-Cardo^||@, and Robert G. Maki^**@

From the Departments of Medicine* and Pathology,^|| Columbia University, New York; the Department of Pathology, New York University School of Medicine, New York; and the Departments of Computational Biology, Pathology, Surgery,^¶ and Medicine,** Memorial Sloan Kettering Cancer Center, New York, New York

^@ To whom correspondence should be addressed. E-mail: cc2791{at}columbia.edu.

	Abstract

The importance of adult stem cells in the development of neoplastic diseases is becoming increasingly well appreciated. We hypothesized that sarcomas of soft tissue could be categorized by their developmental/differentiation status from stem cell to mature tissue, similar to the hematological malignancies. We conducted gene expression analyses during in vitro differentiation of human mesenchymal stem cells into adipose tissue, as a representative mature connective tissue, and identified genes whose expression changed significantly during adipogenesis. Gene clustering and distance correlation analysis allowed the assignment of a unique time point during adipogenesis that strongly correlates to each of the four major liposarcoma subtypes. Using a novel gene expression strategy, in which liposarcomas are compared to their corresponding adipocytic maturing cells, we identified a group of genes overexpressed in liposarcomas that indicate the stage of differentiation arrest, ie, sharing a similar expression profile to adipocytic cells at a corresponding stage of differentiation, and a distinct set of genes overexpressed in liposarcomas that are not found in the corresponding stage of differentiation. We propose that the latter set is enriched for candidate transformation-associated genes. Our results indicate that a degree of developmental maturity can be quantitatively assigned to solid tumors, supporting the notion that transformation of a solid tumor stem cell can occur at distinct stages of maturation.