title: Recurrent amplification at 7q21.2 Targets CDK6 gene in primary myxofibrosarcomas and identifies CDK6 overexpression as an independent adverse prognosticator.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Anatomic Pathology, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Jen-Wei
authors.initials: JW
authors.lastname: Tsai
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
authors.forename: Yu-Chien
authors.initials: YC
authors.lastname: Kao
authors.forename: Jun-Wen
authors.initials: JW
authors.lastname: Wang
authors.forename: Fu-Min
authors.initials: FM
authors.lastname: Fang
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Wang
authors.forename: Wen-Ren
authors.initials: WR
authors.lastname: Wu
authors.forename: Li-Ching
authors.initials: LC
authors.lastname: Wu
authors.forename: Chung-Hsi
authors.initials: CH
authors.lastname: Hsing
authors.forename: Shau-Hsuan
authors.initials: SH
authors.lastname: Li
authors.forename: Shih-Chen
authors.initials: SC
authors.lastname: Yu
authors.forename: Jui
authors.initials: J
authors.lastname: Lan
authors.forename: Hsuan-Ying
authors.initials: HY
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009236:Myxosarcoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D060888:Real-Time Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6