Proffered Papers— Basic Science/Biology

CLINICO-PATHOLOGICAL AND BIOLOGICAL ANALYSES OF THE CHOP-RELATED FUSION GENES IN MYXOID LIPOSARCOMAS

Hosaka T_1,2, Kanoe H_1,2, Nakamura T2, Toguchida J_1,2(₁Institute for Frontier Medical Science and ₂Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan, 606-8507)

The characteristic t(12;16)(q13;p11) or t(12;22)(q13;q12) chromosomal translocations, which lead to gene fusions that encode the TLS-CHOP or EWS-CHOP chimeric protein respectively, are associated with human myxoid/round cell liposarcomas. However, the role of those chimeric proteins in the development of liposarcomas still remains to be solved. To address this issue, we have performed the mutation analysis using clinical specimens, and also conducted the transformation experiment using fusion genes detected in the mutation analysis. First, we have performed reverse transcription-polymerase chain reaction to detect the TLS-CHOP or EWS-CHOP fusion transcripts in 26 liposarcomas which were diagnosed as either myxoid or round cell type. TLS-CHOP fusion transcrips were detected in 17 cases with four different subtypes, EWS-CHOP fusion transcrips were detected in three cases with two different subtypes, and no fusion transcript was detected in six cases. There was no significant correlation between any clinical or pathological findings and the subtypes of TLS-CHOP fusion transcripts. However, two cases with a novel type of EWS-CHOP fusion transcript, which was created by the fusion between EWS exon 10 and CHOP exon 2, demonstrated enormously huge tumors at the diagnosis, and both tumors were treated effectively by chemotherapy. As in vitro studies, we have cloned entire cDNAs of four different TLS-CHOP transcripts and introduced them to 3T3-L1 preadipocytes by retroviral transduction. These cells had no apparent growth advantage, and no colonies were found in the soft agar. However, the adipogenic differentiation was unable to be induced in vitro. DOL54, one of downstream targets of TLS-CHOP genes, was upregulated in these cells. These results suggested that the function of TLS-CHOP gene in the development of liposarcomas is other than growth progression.