Recurrent amplification at 7q21.2 targets CDK6 gene in primary myxofibrosarcomas and identifies CDK6 overexpression as an independent adverse prognosticator

Jen Wei Tsai, Chien Feng Li, Yu-Chien Kao, Jun Wen Wang, Fu Min Fang, Yu Hui Wang, Wen Ren Wu, Li Ching Wu, Chung Hsi Hsing, Shau Hsuan Li, Shih Chen Yu, Jui Lan, Hsuan Ying Huang

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Abstract

Background: Myxofibrosarcoma is genetically complex and remains obscure in molecular determinants of clinical aggressiveness. Our prior study revealed recurrent gains of 7q in myxofibrosarcomas where MET and CDK6 genes displayed increased DNA copies. Previously, we demonstrated the implication of MET overexpression, prompting us to further elucidate the roles of CDK6 in myxofibrosarcomas. Materials: On tissue microarrays, CDK6 immunoexpression was assessable in 77 primary tumors, 55 of which were successfully quantified for CDK6 and MET genes by real-time PCR using genomic DNA extracted from laser-microdissected tumor cells. Gene status and protein expression of CDK6 were correlated with each other, clinicopathological variables, metastasis-free survival (MFS), and disease-specific survival (DSS). Results: Protein overexpression and gene amplification of CDK6, which were detected in 21 of 77 (27.2 %) and 13 of 55 cases (23.6 %), respectively, were highly related to each other (p <.001) and associated with higher grades (overexpression, p = .004; amplification, p = .014). There was a strong correlation between CDK6 and MET gene copies (p <.001, r = 0.0714). Importantly, CDK6 protein overexpression (MFS, p = .0002; DSS, p = .0015) and gene amplification (MFS, p = .0001; DSS, p = .0083) were both univariately associated with worse outcomes. Together with nonextremity location and AJCC stage III disease, CDK6 overexpression independently portended inferior MFS (p = .0015, risk ratio [RR] = 7.411). This aberration, along with nonextremity location, was also an independent adverse prognosticator of DSS (p = .0069, RR = 6.006). Conclusions: In approximately a quarter of primary myxofibrosarcomas, CDK6 overexpression is mostly driven by gene amplification on 7q, associated with adverse prognosticators, and independently predictive of worse outcomes, highlighting its possible causative role in tumor aggressiveness.

Original languageEnglish
Pages (from-to)2716-2725
Number of pages10
JournalAnnals of Surgical Oncology
Volume19
Issue number8
DOIs
Publication statusPublished - Aug 2012

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ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Tsai, J. W., Li, C. F., Kao, Y-C., Wang, J. W., Fang, F. M., Wang, Y. H., Wu, W. R., Wu, L. C., Hsing, C. H., Li, S. H., Yu, S. C., Lan, J., & Huang, H. Y. (2012). Recurrent amplification at 7q21.2 targets CDK6 gene in primary myxofibrosarcomas and identifies CDK6 overexpression as an independent adverse prognosticator. Annals of Surgical Oncology, 19(8), 2716-2725. https://doi.org/10.1245/s10434-012-2317-3