Transcriptomic analysis identifies organ-specific metastasis genes and pathways across different primary sites

Abstract

Background: Metastasis is the most devastating stage of cancer progression and often shows a preference for specific organs.

Methods: To reveal the mechanisms underlying organ-specific metastasis, we systematically analyzed gene expression profiles for three common metastasis sites across all available primary origins. A rank-based method was used to detect differentially expressed genes between metastatic tumor tissues and corresponding control tissues. For each metastasis site, the common differentially expressed genes across all primary origins were identified as organ-specific metastasis genes.

Results: Pathways enriched by these genes reveal an interplay between the molecular characteristics of the cancer cells and those of the target organ. Specifically, the neuroactive ligand-receptor interaction pathway and HIF-1 signaling pathway were found to have prominent roles in adapting to the target organ environment in brain and liver metastases, respectively. Finally, the identified organ-specific metastasis genes and pathways were validated using a primary breast tumor dataset. Survival and cluster analysis showed that organ-specific metastasis genes and pathways tended to be expressed uniquely by a subgroup of patients having metastasis to the target organ, and were associated with the clinical outcome.

Conclusions: Elucidating the genes and pathways underlying organ-specific metastasis may help to identify drug targets and develop treatment strategies to benefit patients.

Keywords: Gene expression profiles; Organ-specific metastasis; Pathway analysis.

Fig. 1

Schema of organ-specific metastasis gene identification. The schema is illustrated by the lung-specific metastasis gene identification

Fig. 2

Similarity of DEGs identified in brain, liver, and lung metastases. Proportionate Venn diagram of DEGs are enumerated and labeled in boxes with colors matching the circles in brain (a), liver (b) and lung metastasis (c)

Fig. 3

Prominent pathways in the process of metastasis. Some of enriched pathways of common DEGs are highlighted in the initialization, dissemination and colonization stage for brain, liver and lung metastasis

Fig. 4

Brain-specific metastasis signature in primary breast tumors. a Hierarchical clustering of 268 primary breast cancer patients was performed with 23 genes in the tight junction pathway. A dendrogram of the tumors is shown on the left, tumors from patients who developed brain metastasis were denoted with asterisk marks; b metastasis-free survival between low- and high-risk groups of primary breast cancer patients distinguished based on the risk score. The p-value of survival difference by logrank test was shown