Oncotarget

Research Papers:

Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma

Naofumi Asano, Akihiko Yoshida, Sachiyo Mitani, Eisuke Kobayashi, Bunsyo Shiotani, Motokiyo Komiyama, Hiroyuki Fujimoto, Hirokazu Chuman, Hideo Morioka, Morio Matsumoto, Masaya Nakamura, Takashi Kubo, Mamoru Kato, Takashi Kohno, Akira Kawai, Tadashi Kondo and Hitoshi Ichikawa _

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Oncotarget. 2017; 8:12941-12952. https://doi.org/10.18632/oncotarget.14652

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Abstract

Naofumi Asano1,2, Akihiko Yoshida3, Sachiyo Mitani4, Eisuke Kobayashi5, Bunsyo Shiotani6, Motokiyo Komiyama7, Hiroyuki Fujimoto7, Hirokazu Chuman5, Hideo Morioka2, Morio Matsumoto2, Masaya Nakamura2, Takashi Kubo8, Mamoru Kato9, Takashi Kohno8,10, Akira Kawai5, Tadashi Kondo1, Hitoshi Ichikawa4,8

1Division of Rare Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

2Department of Orthopaedic Surgery, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan

3Department of Pathology and Clinical Laboratory, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan

4Department of Clinical Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

5Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan

6Division of Genetics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

7Department of Urology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan

8Division of Translational Genomics, National Cancer Center-Exploratory Oncology Research and Clinical Trial Center, Chuo-ku, Tokyo 104-0045, Japan

9Department of Bioinformatics, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

10Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan

Correspondence to:

Hitoshi Ichikawa, email: [email protected]

Keywords: liposarcoma, well-differentiated liposarcoma, dedifferentiated liposarcoma, next-generation sequencing, receptor tyrosine kinase

Received: September 26, 2016     Accepted: January 08, 2017     Published: January 14, 2017

ABSTRACT

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer-related genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.


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