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Clin Cancer Res:预测人类口腔癌侵略性的基因签名

来源:生物谷 2014-08-24 12:37

2014年8月25日讯 /生物谷BIOON/--华盛顿大学医学院研究人员通过研究小鼠口腔癌,研究人员已经找到一种方法来,预测人类中类似肿瘤的攻击性,这对诊断测试、指导治疗有重要意义。所有晚期口腔癌患者都接受类似的治疗,耳鼻喉科副教授Ravindra Uppaluri博士说:有些接受手术,放疗和化疗治疗后效果好,但有些病人没有得到很好的治疗效益。我们感兴趣的是找出其中原因。

在Clinical Cancer Research杂志上的报告中,研究人员发现对于癌症扩散相关的基因表达,人类口腔癌与小鼠口腔癌中有着一致的表达模式。分析人类口腔癌样本的基因数据,他们也发现了与癌症积极扩散相关的基因标记。在新研究中,不是用基因方法来诱发小鼠肿瘤,研究小组反复涂抹一种已知的致癌物质,以与人类发生口腔癌大致相同的方式,来诱发小鼠癌症。

口腔癌病人往往有烟草和酒精的使用,烟草和酒精的使用会推动这些肿瘤的发展,Uppaluri说:我们认为小鼠暴露于致癌物将更有可能产生与人类相似种类的肿瘤。研究人员,表明暴露于致癌物质下,小鼠有时发生的肿瘤没有蔓延,但有时会有激进的转移性肿瘤。Uppaluri团队试图找出小鼠肿瘤和人类肿瘤中是否存在相似的基因。他们将小鼠肿瘤序列与癌症基因组图谱(TCGA)中的人数据集进行比较。

当我们测序这些肿瘤,我们发现了很多存在于小鼠肿瘤中的遗传突变,也被发现在人口腔癌中。进一步分析鉴定出在小鼠肿瘤或人肿瘤中,与更积极肿瘤相关的约120个基因表达中的一个共同基因签名。研究人员使用从324患者中采集的数据来证实这个基因签名。随后,利用在华盛顿大学接受治疗的口腔癌患者样本,利用他们的基因签名开发新的测试以确认侵袭性肿瘤,结果发现准确率高达约93%。(生物谷Bioon.com)

A surprising cross-species conservation in the genomic landscape of mouse and human oral cancer identifies a transcriptional signature predicting metastatic disease.

Onken MD,et al.

Abstract
PURPOSE:
Improved understanding of the molecular basis underlying oral squamous cell carcinoma (OSCC) aggressive growth has significant clinical implications. Herein, cross-species genomic comparison of carcinogen-induced murine and human OSCCs with indolent or metastatic growth yielded results with surprising translational relevance.
EXPERIMENTAL DESIGN:
Murine OSCC cell lines were subjected to next-generation sequencing (NGS) to define their mutational landscape, to define novel candidate cancer genes, and to assess for parallels with known drivers in human OSCC. Expression arrays identified a mouse metastasis signature, and we assessed its representation in four independent human datasets comprising 324 patients using weighted voting and gene set enrichment analysis. Kaplan-Meier analysis and multivariate Cox proportional hazards modeling were used to stratify outcomes. A quantitative real-time PCR assay based on the mouse signature coupled to a machine-learning algorithm was developed and used to stratify an independent set of 31 patients with respect to metastatic lymphadenopathy.
RESULTS:
NGS revealed conservation of human driver pathway mutations in mouse OSCC, including in Trp53, mitogen-activated protein kinase, phosphoinositide 3-kinase, NOTCH, JAK/STAT, and Fat1-4. Moreover, comparative analysis between The Cancer Genome Atlas and mouse samples defined AKAP9, MED12L, and MYH6 as novel putative cancer genes. Expression analysis identified a transcriptional signature predicting aggressiveness and clinical outcomes, which were validated in four independent human OSCC datasets. Finally, we harnessed the translational potential of this signature by creating a clinically feasible assay that stratified patients with OSCC with a 93.5% accuracy.
CONCLUSIONS:
These data demonstrate surprising cross-species genomic conservation that has translational relevance for human oral squamous cell cancer.

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