Pathway-based Analysis of the Hidden Genetic Heterogeneities in Cancers

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• 作者：Xiaolei Zhao¹ ; ^# ; Shouqiang Zhong² ; ^# ; Xiaoyu Zuo³ ; Meihua Lin¹ ; Jiheng Qin¹ ; Yizhao Luan¹ ; Naizun Zhang² ; Yan Liang² ; ^{lye30668@aliyun.com" class="auth_mail} ; Shaoqi Rao¹ ; ³ ; ^{raoshaoq@gdmc.edu.cn" class="auth_mail}
• 关键词：Genetic heterogeneity ; Pathway-based approach ; Sample partitioning ; Enrichment analysis ; Survival analysis ; Cancer
• 刊名：Genomics, Proteomics Bioinformatics
• 出版年：February, 2014
• 年：2014
• 卷：12
• 期：1
• 页码：31-38
• 全文大小：565 K

文摘

Many cancers apparently showing similar phenotypes are actually distinct at the molecular level, leading to very different responses to the same treatment. It has been recently demonstrated that pathway-based approaches are robust and reliable for genetic analysis of cancers. Nevertheless, it remains unclear whether such function-based approaches are useful in deciphering molecular heterogeneities in cancers. Therefore, we aimed to test this possibility in the present study. First, we used a NCI60 dataset to validate the ability of pathways to correctly partition samples. Next, we applied the proposed method to identify the hidden subtypes in diffuse large B-cell lymphoma (DLBCL). Finally, the clinical significance of the identified subtypes was verified using survival analysis. For the NCI60 dataset, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Subsequently, for a DLBCL dataset, we identified three hidden subtypes that showed very different 10-year overall survival rates (90%, 46% and 20%) and were highly significantly (P = 0.008) correlated with the clinical survival rate. This study demonstrated that the pathway-based approach is promising for unveiling genetic heterogeneities in complex human diseases.