Table 2.
Pathway analysis results for the colorectal cancer (CRC) dataset (adjusted p < 0.05).
| ID | Pathway | % CGC genes | pathfindR | DAVID | SPIA | GSEA | GSEAPreranked | Brief Description |
|---|---|---|---|---|---|---|---|---|
| hsa04974 | Protein digestion and absorption | 5.56 | <0.001 | 0.01573699 | – | – | – | |
| hsa04512 | ECM-receptor interaction | 6.1 | <0.001 | 0.00010652 | <0.001 | 0.3232827 | 0.92760116 | The extracellular matrix modulates the hallmarks of cancer (Pickup et al., 2014). |
| hsa04380 | Osteoclast differentiation | 21.26 | <0.001 | – | 0.418726575 | – | – | |
| hsa05205 | Proteoglycans in cancer | 27.86 | <0.001 | 0.02168567 | – | – | – | Proteoglycans play roles in modulating cancer progression, invasion and metastasis (Iozzo and Sanderson, 2011). |
| hsa05130 | Pathogenic Escherichia coli infection | 10.91 | <0.001 | 0.25769925 | 0.015730997 | 0.23110063 | 1 | Pathogenic E. coli is claimed to be a cofactor in pathogenesis of colorectal cancer (Bonnet et al., 2014). |
| hsa00280 | Valine, leucine and isoleucine degradation | 2.08 | <0.001 | <0.001 | – | – | – | Degradation of branched chain amino acids could play an important role in the energy supply of cancer cells (Antanaviciute et al., 2017). |
| hsa04010 | MAPK signaling pathway | 17.97 | <0.001 | 0.08238577 | 0.004151739 | 0.28760567 | 1 | MAPK signaling plays an important part in progression of colorectal cancer (Fang and Richardson, 2005). |
| hsa04520 | Adherens junction | 31.94 | <0.001 | 0.0852993 | – | 0.39334586 | 0.98078984 | Dysregulation of the adherens junction system has particular implications in transformation and tumor invasion (Knights et al., 2012). |
| hsa04810 | Regulation of actin cytoskeleton | 15.02 | <0.001 | 0.01469723 | 0.004105905 | 0.31124064 | 1 | Regulation of actin cytoskeleton is dysregulated in cancer cell migration and invasion (Yamaguchi and Condeelis, 2007). |
| hsa05166 | Human T-cell leukemia virus 1 infection | 27.4 | <0.001 | – | 0.858709076 | – | – | |
| hsa04510 | Focal adhesion | 19.1 | <0.001 | <0.001 | <0.001 | 0.2348305 | 0.95611423 | Cancer cells exhibit highly altered focal adhesion dynamics (Maziveyi and Alahari, 2017). |
| hsa04540 | Gap junction | 19.32 | <0.001 | 0.03853227 | 0.009701705 | 0.24327032 | 0.9830453 | Deficiencies in cell-to-cell communication, particularly gap junctional intercellular communication are observed in CRC (Bigelow and Nguyen, 2014). |
| hsa05012 | Parkinson disease | 6.34 | <0.001 | 0.28728621 | 0.025978875 | – | 0.91026866 | |
| hsa04662 | B cell receptor signaling pathway | 42.25 | <0.001 | – | 0.500093708 | 0.27041057 | 1 | |
| hsa00071 | Fatty acid degradation | 6.82 | <0.001 | <0.001 | – | – | – | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer (Wen et al., 2017). |
| hsa04658 | Th1 and Th2 cell differentiation | 19.57 | <0.001 | – | – | – | – | T helper cells are important in cancer immunity (Knutson and Disis, 2005). |
| hsa05165 | Human papillomavirus infection | 19.09 | <0.001 | – | – | – | – | |
| hsa05161 | Hepatitis B | 31.29 | <0.001 | – | – | – | – | |
| hsa00640 | Propanoate metabolism | 0 | <0.001 | <0.001 | – | – | – | |
| hsa04151 | PI3K-Akt signaling pathway | 21.47 | <0.001 | 0.07244833 | – | – | – | PI3K-Akt signaling is deregulated in CRC (Danielsen et al., 2015; Zhang et al., 2017a). |
| hsa04660 | T cell receptor signaling pathway | 31.68 | <0.001 | – | 0.698350894 | 0.44643503 | 0.965013 | T-cell receptor signaling modulates control of anti-cancer immunity (Cronin and Penninger, 2007). |
| hsa04659 | Th17 cell differentiation | 26.17 | <0.001 | – | – | – | – | A unique change of Th17 cells was observed in the progression of CRC (Wang et al., 2012). |
| hsa04933 | AGE-RAGE signaling pathway in diabetic complications | 31 | <0.001 | – | – | – | – | |
| hsa04657 | IL-17 signaling pathway | 9.68 | <0.001 | – | – | – | – | IL-17 is considered as a promoter factor in CRC progression (Wu et al., 2013). |
| hsa04625 | C-type lectin receptor signaling pathway | 27.88 | <0.001 | – | – | – | – | C-Type lectin receptors may be targeted for cancer immunity (Yan et al., 2015). |
| hsa05167 | Kaposi sarcoma-associated herpesvirus infection | 24.73 | <0.001 | – | – | – | – | |
| hsa05170 | Human immunodeficiency virus 1 infection | 16.98 | <0.001 | – | – | – | – | |
| hsa04921 | Oxytocin signaling pathway | 13.16 | <0.001 | 0.1513106 | – | – | – | |
| hsa05168 | Herpes simplex infection | 10.81 | <0.001 | – | 0.840617856 | – | – | |
| hsa04668 | TNF signaling pathway | 18.18 | <0.001 | – | – | – | – | TNF-α was shown to promote colon cancer cell migration and invasion (Zhao and Zhang, 2018). |
| hsa04022 | cGMP-PKG signaling pathway | 11.04 | <0.001 | 0.00352246 | – | – | – | cGMP-PKG signaling inhibits cell proliferation and induces apoptosis (Fajardo et al., 2014). |
| hsa00650 | Butanoate metabolism | 0 | <0.001 | <0.001 | – | – | – | Butanoate has the ability to inhibit carcinogenesis (Goncalves and Martel, 2013). |
| hsa05132 | Salmonella infection | 8.14 | <0.001 | – | 0.524757851 | – | – | |
| hsa05014 | Amyotrophic lateral sclerosis (ALS) | 15.69 | <0.001 | 0.36800171 | 0.200174194 | 0.27973756 | 1 | |
| hsa04530 | Tight junction | 11.18 | <0.001 | 0.0915822 | 0.02704172 | 0.27459267 | 0.98746127 | Dysregulation of tight junctions promote tumorigenesis as well as tumor progression in colorectal cancer (Hollande and Papin, 2013). |
| hsa04150 | mTOR signaling pathway | 16.45 | <0.001 | – | 0.999999998 | 0.31433496 | 1 | mTOR signaling is accepted as one of the primary mechanisms for sustaining tumor outgrowth and metastasis and is dysregulated in many cancers, including colorectal cancer (Francipane and Lagasse, 2014). |
| hsa05120 | Epithelial cell signaling in Helicobacter pylori infection | 14.71 | <0.001 | – | 0.552502996 | 0.327181 | 1 | |
| hsa05418 | Fluid shear stress and atherosclerosis | 18.71 | <0.001 | – | – | – | – | |
| hsa04015 | Rap1 signaling pathway | 18.93 | <0.001 | – | – | – | – | Rap1 signaling has roles in tumor cell migration and invasion (Zhang et al., 2017b). |
| hsa05164 | Influenza A | 15.79 | <0.001 | – | 0.999999998 | – | – | |
| hsa05100 | Bacterial invasion of epithelial cells | 22.97 | <0.001 | – | 0.167771421 | – | – | |
| hsa05146 | Amebiasis | 12.5 | <0.001 | – | 0.418726575 | – | – | |
| hsa00380 | Tryptophan metabolism | 2.5 | <0.001 | 0.0036283 | – | – | – | Tryptophan metabolism is a promising target for immunotherapy in CRC (Santhanam et al., 2016). |
| hsa04072 | Phospholipase D signaling pathway | 20.55 | 0.001079935 | – | – | – | – | Phospholipase D signaling has roles in cell migration, invasion and metastasis (Gomez-Cambronero, 2014). |
| hsa04014 | Ras signaling pathway | 18.1 | 0.001165472 | – | – | – | – | Ras signaling has roles in colorectal cancer progression, treatment response, prognosis (Zenonos and Kyprianou, 2013). |
| hsa05210 | Colorectal cancer | 51.16 | 0.00129243 | – | 0.177026287 | 0.5272962 | 1 | The pathway of the disease. |
| hsa05200 | Pathways in cancer | 26.81 | 0.001394025 | 0.01610123 | 0.004421859 | 0.23207118 | 0.99618906 | “Meta”-pathway of cancer pathways. |
| hsa05169 | Epstein-Barr virus infection | 21.39 | 0.001483431 | – | 0.999999998 | – | – | |
| hsa04934 | Cushing syndrome | 22.73 | 0.002134647 | – | – | – | – | |
| hsa00190 | Oxidative phosphorylation | 3.76 | 0.002190056 | – | – | – | 1 | Glucose metabolism is altered in cancers, including CRC (Fang and Fang, 2016). |
| hsa04144 | Endocytosis | 11.48 | 0.00223191 | – | – | 0.74809563 | 0.9971049 | |
| hsa04722 | Neurotrophin signaling pathway | 26.05 | 0.00225063 | – | 0.869732385 | 0.22082567 | 0.9303874 | Neurotrophin signaling and related factors were found to clearly exert several biological and clinical features in CRC (Akil et al., 2016). |
| hsa04926 | Relaxin signaling pathway | 20.77 | 0.002413722 | – | – | – | – | Relaxin signaling has a role in tumor cell growth and differentiation (Silvertown et al., 2003). |
| hsa04024 | cAMP signaling pathway | 14.57 | 0.002417989 | 0.37342574 | – | – | – | Dysregulation cAMP signaling was implicated in many cancer types, including CRC (Löffler et al., 2008; Fajardo et al., 2014). |
| hsa04310 | Wnt signaling pathway | 17.72 | 0.002418113 | – | 0.068851256 | 0.3056234 | 1 | Wnt signaling is a key player in many cancers, responsible for maintenance of cancer stem cells, metastasis and immune control (Zhan et al., 2017). |
| hsa05226 | Gastric cancer | 30.87 | 0.00267019 | – | – | – | – | |
| hsa04392 | Hippo signaling pathway - multiple species | 17.24 | 0.002915258 | – | – | – | – | Hippo signaling is involved in the control of intestinal stem cell proliferation and colorectal cancer development (Wierzbicki and Rybarczyk, 2015). |
| hsa04390 | Hippo signaling pathway | 16.23 | 0.003135632 | – | – | – | – | Hippo signaling is involved in the control of intestinal stem cell proliferation and colorectal cancer development (Wierzbicki and Rybarczyk, 2015). |
| hsa00630 | Glyoxylate and dicarboxylate metabolism | 0 | 0.003236188 | 0.30407411 | – | – | – | |
| hsa04110 | Cell cycle | 23.39 | 0.003442925 | – | 0.987280486 | – | 0.9898676 | Dysregulation of the cell cycle is implicated in the biology of many cancers, including CRC (Hartwell and Kastan, 1994; Collins et al., 1997; Jarry et al., 2004). |
| hsa04932 | Non-alcoholic fatty liver disease (NAFLD) | 13.42 | 0.003808796 | – | – | – | – | |
| hsa05142 | Chagas disease (American trypanosomiasis) | 21.36 | 0.003899445 | – | 0.937326751 | – | – | |
| hsa00410 | beta-Alanine metabolism | 3.23 | 0.005120816 | 0.00196409 | – | – | 1 | |
| hsa04670 | Leukocyte transendothelial migration | 16.07 | 0.005646255 | 0.35563014 | 0.167771421 | 0.27631387 | 1 | |
| hsa00620 | Pyruvate metabolism | 5.13 | 0.00565919 | 0.09639534 | – | – | – | Glucose metabolism is altered in cancers, including CRC (Fang and Fang, 2016). |
| hsa04114 | Oocyte meiosis | 7.2 | 0.006872183 | – | 0.792716868 | 0.72884667 | 0.97175264 | |
| hsa05215 | Prostate cancer | 51.55 | 0.007778647 | – | 0.598712628 | 0.32108408 | 1 | |
| hsa04210 | Apoptosis | 22.06 | 0.007963488 | – | 0.869732385 | – | – | Abnormalities in apoptotic function contribute to both the pathogenesis of colorectal cancer and its resistance to chemotherapeutic drugs and radiotherapy (Watson, 2004). |
| hsa05140 | Leishmaniasis | 10.81 | 0.008480037 | – | 0.999999998 | 0.24636032 | 1 | |
| hsa05222 | Small cell lung cancer | 27.96 | 0.008933391 | – | 0.120809416 | 0.45156074 | 1 | |
| hsa05160 | Hepatitis C | 22.58 | 0.010464676 | – | 0.869732385 | – | – | |
| hsa05031 | Amphetamine addiction | 13.24 | 0.010805065 | – | 0.107609007 | – | – | |
| hsa04621 | NOD-like receptor signaling pathway | 6.74 | 0.011387668 | – | 0.999999998 | 0.5148187 | 0.9774175 | NOD-like receptors are accepted as master regulators of inflammation and cancer (Saxena and Yeretssian, 2014). |
| hsa04914 | Progesterone-mediated oocyte maturation | 16.16 | 0.011933047 | – | 0.857467386 | 0.5950144 | 0.9922697 | |
| hsa04923 | Regulation of lipolysis in adipocytes | 18.52 | 0.011957867 | 0.19643837 | – | – | – | Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer (Wen et al., 2017). |
| hsa04071 | Sphingolipid signaling pathway | 18.64 | 0.012088886 | – | – | – | – | Sphingolipids have emerging roles in CRC (García-Barros et al., 2014). |
| hsa05016 | Huntington disease | 10.88 | 0.013246653 | – | 0.494422017 | – | 1 | |
| hsa05030 | Cocaine addiction | 16.33 | 0.014430369 | – | 0.310528247 | – | – | |
| hsa04270 | Vascular smooth muscle contraction | 12.4 | 0.014703261 | 0.01450931 | <0.001 | 0.31157959 | 0.91536194 | |
| hsa04915 | Estrogen signaling pathway | 22.06 | 0.014973032 | – | – | – | – | |
| hsa04664 | Fc epsilon RI signaling pathway | 29.41 | 0.016512816 | – | 0.552502996 | 0.7568524 | 0.99502826 | |
| hsa05211 | Renal cell carcinoma | 44.93 | 0.017251888 | – | 0.107609007 | 0.59724545 | 1 | |
| hsa05202 | Transcriptional misregulation in cancer | 44.09 | 0.017926078 | – | 0.329766057 | – | – | Core cancer pathway |
| hsa04913 | Ovarian steroidogenesis | 4.08 | 0.021805547 | – | – | – | – | |
| hsa04620 | Toll-like receptor signaling pathway | 14.42 | 0.023494048 | – | 0.968714181 | 0.44691193 | 1 | Toll-like receptor signaling pathway is being considered as a potential therapeutic target in colorectal cancer (Moradi-Marjaneh et al., 2018). |
| hsa04370 | VEGF signaling pathway | 33.9 | 0.025228423 | – | 0.768939947 | 0.53752804 | 1 | Dysregulation of VEGF signaling is observed in numerous cancers, including CRC (Sun, 2012; Stacker and Achen, 2013). |
| hsa04020 | Calcium signaling pathway | 9.57 | 0.025565655 | 0.33050764 | 0.057419238 | 0.3367621 | 0.9716838 | Alterations of calcium signaling modulate tumor initiation, angiogenesis, progression and metastasis (Cui et al., 2017). |
| hsa05224 | Breast cancer | 31.29 | 0.028494806 | – | – | – | – | |
| hsa04630 | JAK-STAT signaling pathway | 24.07 | 0.029068433 | – | 0.494422017 | 0.40343955 | 1 | Jak-STAT signaling is involved in immune function and cell growth and has an important role in colorectal cancer (Slattery et al., 2013). |
| hsa04723 | Retrograde endocannabinoid signaling | 4.05 | 0.029254258 | – | 0.147248603 | – | – | |
| hsa04622 | RIG-I-like receptor signaling pathway | 7.14 | 0.030848585 | – | 0.524757851 | 0.95792913 | – | RIG-I-like receptors are important in immune signaling (Loo and Gale, 2011). |
| hsa04720 | Long-term potentiation | 22.39 | 0.031734969 | – | 0.899457922 | 0.7634754 | 0.9743132 | |
| hsa04360 | Axon guidance | 14.36 | 0.032363714 | 0.14566283 | 0.03397083 | 0.31695387 | 0.98838806 | |
| hsa04115 | p53 signaling pathway | 33.33 | 0.033554867 | – | 0.869732385 | – | 0.9952885 | p53 signaling influences many key processes such as cell cycle arrest, apoptosis, and angiogenesis (Slattery et al., 2018). |
| hsa05131 | Shigellosis | 10.77 | 0.033710491 | – | 0.87420689 | – | – | |
| hsa05203 | Viral carcinogenesis | 23.38 | 0.036540488 | – | 0.999999998 | – | – | |
| hsa05416 | Viral myocarditis | 18.64 | 0.038063956 | – | 0.418726575 | 0.27175233 | 0.9940278 | |
| hsa04666 | Fc gamma R-mediated phagocytosis | 20.88 | 0.039418918 | – | 0.141340043 | 0.32853782 | – | |
| hsa00010 | Glycolysis / Gluconeogenesis | 1.47 | 0.044512411 | 0.35158586 | – | – | 1 | Glucose metabolism is altered in cancers, including CRC (Fang and Fang, 2016). |
| hsa01212 | Fatty acid metabolism | 0 | – | <0.001 | – | – | 1 | |
| hsa01130 | Biosynthesis of antibiotics | 0 | – | <0.001 | – | – | – | |
| hsa04924 | Renin secretion | 7.69 | 0.050814742 | <0.001 | – | – | – | |
| hsa05414 | Dilated cardiomyopathy | 8.89 | 0.211547395 | 0.10754894 | 0.009508921 | 0.29030624 | 0.95637035 | |
| hsa03320 | PPAR signaling pathway | 4.05 | – | 0.11340534 | 0.015730997 | 0.5118186 | 0.98862046 | PPARδ acts as a tumor suppressor in colorectal cancer (You et al., 2015). |
| hsa01200 | Carbon metabolism | 0 | – | 0.003293423 | – | – | – | |
| hsa01100 | Metabolic pathways | 0 | – | 0.015541794 | – | – | – | Metabolic reprogramming has consequences at the cellular and molecular level with implications for cancer initiation and growth (Hagland et al., 2013) |
“ID” indicates the Kyoto Encyclopedia of Genes and Genomes (KEGG) ID for the enriched pathway, whereas “Pathway” indicates the KEGG pathway name. “% CGC genes” indicates the percentage of Cancer Gene Census (CGC) genes in the pathway. The lowest Bonferroni-adjusted p value for pathfindR analysis is provided in “pathfindR,” the false discovery rate (FDR)-adjusted p value for Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis is provided in “DAVID,” the FDR-adjusted p value for Signaling Pathway Impact Analysis (SPIA) is presented in “SPIA,” and the FDR-adjusted p values for Gene Set Enrichment Analysis (GSEA) and GSEAPreranked are presented in “GSEA” and “GSEAPreranked,” respectively. Significant p values (i.e., adjusted p value < 0.05) are given in bold font. “-“ indicates the pathway was not found to be enriched by the given tool. If a pathway is relevant to CRC, a brief description of its relevance is provided in “Brief Description.”