原发性黏液纤维肉瘤中 7q21.2 处的反复扩增靶向 CDK6 基因，并鉴定出 CDK6 过表达是独立的不良预后预测因子。

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

机构信息

Department of Anatomic Pathology, E-Da Hospital, Kaohsiung, Taiwan.

出版信息

Ann Surg Oncol. 2012 Aug;19(8):2716-25. doi: 10.1245/s10434-012-2317-3. Epub 2012 Apr 3.

DOI:10.1245/s10434-012-2317-3

PMID:22476749

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.

摘要

背景

黏液纤维肉瘤的遗传较为复杂，其临床侵袭性的分子决定因素仍不清楚。我们之前的研究显示，黏液纤维肉瘤中存在 7q 的反复增益，其中 MET 和 CDK6 基因的 DNA 拷贝增加。先前，我们证明了 MET 过表达的意义，这促使我们进一步阐明 CDK6 在黏液纤维肉瘤中的作用。

材料

在组织微阵列上，77 例原发肿瘤中可评估 CDK6 的免疫表达，其中 55 例成功地通过使用从激光显微切割肿瘤细胞中提取的基因组 DNA 通过实时 PCR 定量检测 CDK6 和 MET 基因。CDK6 基因状态和蛋白表达相互关联，并与临床病理变量、无复发生存（MFS）和疾病特异性生存（DSS）相关。

结果

在 77 例病例中的 21 例（27.2%）和 55 例病例中的 13 例（23.6%）中检测到 CDK6 的蛋白过表达和基因扩增，这两者高度相关（p<0.001），并且与较高的分级相关（过表达，p=0.004；扩增，p=0.014）。CDK6 与 MET 基因拷贝之间存在很强的相关性（p<0.001，r=0.0714）。重要的是，CDK6 蛋白过表达（MFS，p=0.0002；DSS，p=0.0015）和基因扩增（MFS，p=0.0001；DSS，p=0.0083）均与不良预后相关。与非肢端位置和 AJCC Ⅲ期疾病一起，CDK6 过表达独立预示着较差的 MFS（p=0.0015，风险比[RR]=7.411）。这种异常与非肢端位置一样，也是 DSS 的独立不良预后因素（p=0.0069，RR=6.006）。