Pathway-based Analysis of the Hidden Genetic Heterogeneities in Cancers

• Main Authors: Xiaolei Zhao, Shouqiang Zhong, Xiaoyu Zuo, Meihua Lin, Jiheng Qin, Yizhao Luan, Naizun Zhang, Yan Liang, Shaoqi Rao
• Format: Article
• Language: English
• Published: Elsevier 2014-02-01
• Series: Genomics, Proteomics & Bioinformatics
• Subjects: Genetic heterogeneity; Pathway-based approach; Sample partitioning; Enrichment analysis; Survival analysis; Cancer
• Online Access: http://www.sciencedirect.com/science/article/pii/S1672022914000023

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.