Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck
Identification of a gene expression signature associated with recurrent disease in squamous cell carcinoma of the head and neck
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DOI：
10.1158/0008-5472.can-03-2144
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发表时间：
2004-01-01
期刊：
影响因子：
11.2
通讯作者：
Gaffney, PM
中科院分区：
文献类型：
--
作者：
Ginos, MA;Page, GP;Gaffney, PM
头颈部鳞状细胞癌（HNSCC）的分子研究已经证明了多种遗传异常，如各种癌基因（Ras，Myc，表皮生长因子受体和细胞周期蛋白D1）的激活，肿瘤抑制基因（TP 53和p16）的失活，以及许多染色体位置的杂合性丢失。尽管有这些观察结果，准确和可靠的生物标志物;预测局部复发风险最高的患者尚未确定。为了鉴定可作为生物标志物的基因表达特征，我们研究了41个来自不同解剖部位的鳞状细胞癌肿瘤（25个原发性和16个局部复发性）和13个来自健康志愿者的正常口腔粘膜活检样本，使用Affytek U133 A基因芯片阵列进行微阵列分析。通过计算广义t检验（P < 0.001）和应用一系列过滤标准来鉴定差异表达的基因，以产生2890个基因的高度判别列表。使用标准软件的层次聚类和图像生成用于可视化基因表达特征。在HNSCC肿瘤中容易鉴定几种基因表达特征，包括与增殖、细胞外基质产生、细胞因子/趋化因子表达和免疫应答相关的特征。特别令人感兴趣的是富集参与肿瘤侵袭和转移的基因的基因表达特征与经历局部复发性疾病的患者的关联。值得注意的是，这些肿瘤还表现出明显缺乏免疫应答特征，表明肿瘤特异性免疫应答的调节可能在局部治疗失败中起作用。这些数据为HNSCC局部治疗失败的新的基于基因表达的生物标志物提供了证据。
Molecular studies of squamous cell carcinoma of the head and neck (HNSCC) have demonstrated multiple genetic abnormalities such as activation of various oncogenes (Ras, Myc, epidermal growth factor receptor, and cyclin D1), tumor suppressor gene inactivation (TP53 and p16), and loss of heterozygosity at numerous chromosomal locations. Despite these observations, accurate and reliable biomarkers; that predict patients at highest risk for local recurrence have yet to be defined. In an effort to identify gene expression signatures that may serve as biomarkers, we studied 41 squamous cell carcinoma tumors (25 primary and 16 locally recurrent) from various anatomical sites and 13 normal oral mucosal biopsy samples from healthy volunteers with microarray analysis using Affymetrix U133A GeneChip arrays. Differentially expressed genes were identified by calculating generalized t tests (P < 0.001) and applying a series of filtering criteria to yield a highly discriminant list of 2890 genes. Hierarchical clustering and image generation using standard software were used to visualize gene expression signatures. Several gene expression signatures were readily identifiable in the HNSCC tumors, including signatures associated with proliferation, extracellular matrix production, cytokine/chemokine expression, and immune response. Of particular interest was the association of a gene expression signature enriched for genes involved in tumor invasion and metastasis with patients experiencing locally recurrent disease. Notably, these tumors also demonstrated a marked absence of an immune response signature suggesting that modulation of tumor-specific immune responses may play a role in local treatment failure. These data provide evidence for a new gene expression-based biomarker of local treatment failure in HNSCC.