Meta-Analysis of Multiple Microarray Datasets Reveals a Common Gene Signature of Metastasis in Solid Tumors

Author: Marla H. Daves, MD

Primary Advisor: Jorge Herskovic, MD, PhD

Committee Members: Elmer V. Bernstam, MD, MSE

Masters thesis, The University of Texas School of Biomedical Informatics at Houston.

Abstract:

Background

Metastasis is the number one cause of cancer deaths. Expression microarrays have been widely used to study metastasis in various types of cancer. We hypothesize that a meta-analysis of publicly available gene expression datasets in various tumor types can identify a signature of metastasis that is common to multiple tumor types. This common signature of metastasis may help us to understand the shared steps in the metastatic process and identify useful biomarkers that could predict metastatic risk.

Methods

We identified 18 publicly available gene expression datasets in the Oncomine database comparing distant metastases to primary tumors in various solid tumors which met our eligibility criteria. We performed a meta-analysis using a modified permutation counting method in order to obtain a common gene signature of metastasis. We then validated this signature in independent datasets using gene set expression comparison analysis with the LS-statistic.

Results

A common metastatic signature of 79 genes was identified in the metastatic lesions compared with primaries with a False Discovery Proportion of less than 0.1. Interestingly, all the genes in the signature, except one, were significantly downregulated, suggesting that overcoming metastatic suppression may be a key feature that is common to all metastatic tumors. Pathway analysis of the significant genes showed that the genes were involved in known metastasis-associated pathways, such as integrin signaling, calcium signaling, and VEGF signaling. To validate the signature, we used an additional six expression datasets that were not used in the discovery study. Our results showed that the signature was significantly enriched in four validation sets with p-values less than 0.05.

Conclusions

We have modified a previously published meta-analysis method and identified a common metastatic signature by comparing primary tumors versus metastases in various tumor types. This approach, as well as the gene signature identified, provides important insights to the common metastatic process and a foundation for future discoveries that could have broad application, such as drug discovery, metastasis prediction, and mechanistic studies.