Concordance of copy number loss and down-regulation of tumor suppressor genes: a pan-cancer study.

Min Zhao,Zhongming Zhao

doi:10.1186/s12864-016-2904-y

Abstract

BackgroundTumor suppressor genes (TSGs) encode the guardian molecules to control cell growth. The genomic alteration of TSGs may cause tumorigenesis and promote cancer progression. So far, investigators have mainly studied the functional effects of somatic single nucleotide variants in TSGs. Copy number variation (CNV) is another important form of genetic variation, and is often involved in cancer biology and drug treatment, but studies of CNV in TSGs are less represented in literature. In addition, there is a lack of a combinatory analysis of gene expression and CNV in this important gene set. Such a study may provide more insights into the relationship between gene dosage and tumorigenesis. To meet this demand, we performed a systematic analysis of CNVs and gene expression in TSGs to provide a systematic view of CNV and gene expression change in TSGs in pan-cancer.ResultsWe identified 1170 TSGs with copy number gain or loss in 5846 tumor samples. Among them, 207 TSGs tended to have copy number loss (CNL), from which fifteen CNL hotspot regions were identified. The functional enrichment analysis revealed that the 207 TSGs were enriched in cancer-related pathways such as P53 signaling pathway and the P53 interactome. We further performed integrative analyses of CNV with gene expression using the data from the matched tumor samples. We found 81 TSGs with concordant CNL events and decreased gene expression in the tumor samples we examined. Remarkably, seven TSGs displayed concordant CNL and gene down-regulation in at least 50 tumor samples: MTAP (212 samples), PTEN (139), MCPH1 (85), FBXO25 (67), SMAD4 (64), TRIM35 (57), and RB1 (54). Specifically to MTAP, this concordance was found in 14 cancer types, an observation that is not much reported in literature yet. Further network-based analysis revealed that these TSGs with concordant CNL and gene down-regulation were highly connected.ConclusionsThis study provides a draft landscape of CNV in pan-cancer. Our findings of systematic concordance between CNL and down-regulation of gene expression may help better understand the TSG biology in tumorigenesis and cancer progression.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2904-y) contains supplementary material, which is available to authorized users.

Highlights

Tumor suppressor genes (TSGs) encode the guardian molecules to control cell growth
Genomic regions with frequent copy number loss in tumor suppressor gene (TSG) in multiple cancer types To systematically survey the somatic Copy number variation (CNV) in TSGs, our pipeline started with a list of 1207 human TSGs from the TSGene 2.0 database [2, 23] (Fig. 1)
In conclusion, our systematic exploration of copy number variations on human TSGs revealed that the copy number loss of TSGs cluster in a few genomics regions

Summary

Introduction

Tumor suppressor genes (TSGs) encode the guardian molecules to control cell growth. There is a lack of a combinatory analysis of gene expression and CNV in this important gene set. Such a study may provide more insights into the relationship between gene dosage and tumorigenesis. Tumor suppressor genes (TSGs) are important guardian genes that protect a normal cell from one step on the path to uncontrolled growth [2, 3]. TSGs may lose their normal functions because of mutations occur at its critical sites. Similar effects can be caused by larger scale mutations, such as copy number variations (CNVs), gene fusions, or structural variants (SVs) [4, 5]. The identification and understanding of TSGs have profound influence to develop the diagnosis biomarkers and effective drugs for cancer therapies

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Discussion

Conclusion