Abstract
Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer.
Highlights
Colorectal cancer (CRC; MIM#114500) ranks third in cancer incidence world-wide with an estimated 1.2 million new cases per year [1]
According to the American Joint Committee on Cancer (AJCC) the 5-year survival rates for patients diagnosed with stage I and stage IV CRC, are 93% and 8% respectively, patient prognosis is highly dependent on the tumor stage at diagnosis [2]
Kyoto Encyclopedia of Genes and Genomes (KEGG) networks significantly deregulated in CRC compared to normal mucosa in both datasets are listed in Table S1 (n = 82)
Summary
Colorectal cancer (CRC; MIM#114500) ranks third in cancer incidence world-wide with an estimated 1.2 million new cases per year [1]. According to the American Joint Committee on Cancer (AJCC) the 5-year survival rates for patients diagnosed with stage I and stage IV CRC, are 93% and 8% respectively, patient prognosis is highly dependent on the tumor stage at diagnosis [2]. CRC develops through distinct histopathological stages from benign precursor lesions to malignant tumors, known as the adenomacarcinoma sequence. The development is driven by progressive accumulation of genetic and epigenetic alterations of specific genes, and conserved signaling networks that exert pleiotropic effects on the cancer cells are often targeted. The most commonly altered genes during CRC development make up the basis for these phenotypes and involve several signaling pathways and networks (Figure 1A)
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