Genomic Alterations and Allelic Imbalances Are Strong Prognostic Predictors in Osteosarcoma
Genomic Alterations and Allelic Imbalances Are Strong Prognostic Predictors in Osteosarcoma
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DOI：
10.1158/1078-0432.ccr-10-0284
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发表时间：
2010-08-15
影响因子：
11.5
通讯作者：
Nathrath, Michaela
中科院分区：
文献类型：
--
作者：
Smida, Jan;Baumhoer, Daniel;Nathrath, Michaela
目的：骨肉瘤是最常见的原发性骨恶性肿瘤，其特征是染色体组型复杂，有许多结构和数量的改变。尽管试图在诊断时建立分子预后标志物，最被接受的预测因素仍然是新辅助化疗后坏死的组织学评价。目前的方法进行了搜索全基因组的杂合性和拷贝数变异，可能有预后和治疗的影响，为骨肉瘤patients.Experimental Design：治疗前活检样本的45例骨肉瘤患者进行了分析，使用Affytek 10 K2高密度单核苷酸多态性阵列。结果：最常见的基因组改变包括染色体6p 21（15.6%），8 q24（15.6%，窝藏MYC），12 q14（11.1%，窝藏CDK 4）的扩增，以及10q21.1（44.4%）的杂合性丢失。所有这些畸变和每个肿瘤的杂合性的总程度与患者的不良结局显着相关，并被用来定义一个染色体改变分期系统，具有上级预测潜力相比，组织学回归grading.Conclusions：单核苷酸多态性分析检测到的结构染色体改变提供了一个简单但强大的参数来预测化疗的反应。因此，拟议的染色体改变分期系统可能有助于更好地预测骨肉瘤患者的临床过程中，在最初的诊断和适应新辅助治疗的患者抵抗目前的协议。临床癌症研究; 16（16）; 4256-67。(C)2010年AACR。
Purpose: Osteosarcoma, the most common primary malignant tumor of the bone, is characterized by complex karyotypes with numerous structural and numerical alterations. Despite attempts to establish molecular prognostic markers at the time of diagnosis, the most accepted predictive factor remains the histologic evaluation of necrosis after neoadjuvant chemotherapy. The present approach was carried out to search for genome-wide recurrent loss of heterozygosity and copy number variations that could have prognostic and therapeutic impact for osteosarcoma patients.Experimental Design: Pretherapeutic biopsy samples of 45 osteosarcoma patients were analyzed using Affymetrix 10K2 high-density single nucleotide polymorphism arrays. Numerical aberrations and allelic imbalances were correlated with the histologically assessed response to therapy and clinical follow-up.Results: The most frequent genomic alterations included amplifications of chromosome 6p21 (15.6%), 8q24 (15.6%, harboring MYC), and 12q14 (11.1%, harboring CDK4), as well as loss of heterozygosity of 10q21.1 (44.4%). All these aberrations and the total degree of heterozygosity of each tumor were significantly associated with an adverse outcome of patients and were used to define a chromosomal alteration staging system with a superior predictive potential compared with the histologic regression grading.Conclusions: Structural chromosomal alterations detected by single nucleotide polymorphism analysis provide a simple but robust parameter to anticipate response to chemotherapy. The proposed chromosomal alteration staging system might therefore help to better predict the clinical course of osteosarcoma patients at the time of initial diagnosis and to adapt neoadjuvant treatment in patients resistant to the current protocols. Clin Cancer Res; 16(16); 4256-67. (C) 2010 AACR.