Abstract
Several studies have already identified the prognostic markers in colorectal cancer (CRC) based on somatic copy number alteration (SCNA). However, very little information is available regarding their value as a prognostic marker. Gene dosage effect is one important mechanism of copy number and dosage-sensitive genes are more likely to behave like driver genes. In this work, we propose a new pipeline to identify the dosage-sensitive prognostic genes in CRC. The RNAseq data, the somatic copy number of CRC from TCGA were assayed to screen out the SCNAs. Wilcoxon rank-sum test was used to identify the differentially expressed genes in alteration samples with |SCNA| > 0.3. Cox-regression was used to find the candidate prognostic genes. An iterative algorithm was built to identify the stable prognostic genes. Finally, the Pearson correlation coefficient was calculated between gene expression and SCNA as the dosage effect score. The cell line data from CCLE was used to test the consistency of the dosage effect. The differential co-expression network was built to discover their function in CRC. A total of six amplified genes (NDUFB4, WDR5B, IQCB1, KPNA1, GTF2E1, and SEC22A) were found to be associated with poor prognosis. They demonstrate a stable prognostic classification in more than 50% threshold of SCNA. The average dosage effect score was 0.5918 ± 0.066, 0.5978 ± 0.082 in TCGA and CCLE, respectively. They also show great stability in different data sets. In the differential co-expression network, these six genes have the top degree and are connected to the driver and tumor suppressor genes. Function enrichment analysis revealed that gene NDUFB4 and GTF2E1 affect cancer-related functions such as transmembrane transport and transformation factors. In conclusion, the pipeline for identifying the prognostic dosage-sensitive genes in CRC was proved to be stable and reliable.
Highlights
Colorectal cancer (CRC), is the 3rd leading cause of cancer-associated deaths in the world (Siegel et al, 2019)
A total of 448 colorectal cancer (CRC) samples with somatic copy number alteration (SCNA) and RNA-seq data were downloaded from The Cancer Genome Atlas (TCGA)
A total of six prognostic dosage-sensitive genes (PDSGs) identified in the present study have the robustness to different SCNA threshold in prognostic classification and have the same dosage effect in CRC cell lines
Summary
Colorectal cancer (CRC), is the 3rd leading cause of cancer-associated deaths in the world (Siegel et al, 2019). SCNA genes are usually considered as the driver gene for cancer development and Dosage-Sensitive Genes in Colorectal Cancer an important factor for the progression of CRC (Wang et al, 2009; Rosenberg et al, 2018; Lee et al, 2019). In addition to this few SCNA genes are being considered as prognostic markers for CRC patients (Roy et al, 2016; Sefrioui et al, 2017). Some of the dosage-sensitive genes (DSGs) such as CD274/PD-L1 gene amplification (Lee et al, 2018b), fibroblast growth factor 1 amplification (Bae et al, 2019), RING-Finger Protein 6 amplification (Steinman et al, 1979), have been shown to be associated with poor prognosis, suggesting DSGs can be considered as prognostic markers
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