Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma
Complex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to h...
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doaj-98b8363a76e044c28d4d721a84b7cccd2020-11-24T22:29:03ZengPeerJ Inc.PeerJ2167-83592018-04-016e457110.7717/peerj.4571Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinomaChaoxing Li0Li Liu1Valentin Dinu2School of Life Sciences, Arizona State University, Tempe, AZ, United States of AmericaDepartment of Biomedical Informatics, Arizona State University, Scottsdale, AZ, United States of AmericaDepartment of Biomedical Informatics, Arizona State University, Scottsdale, AZ, United States of AmericaComplex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to have a robust topological structure under normal physiological conditions. However, the pathway’s topological structure could be altered under some pathological condition. It is well known that a normal biological network includes a small number of well-connected hub nodes and a large number of nodes that are non-hubs. In addition, it is reported that the loss of connectivity is a common topological trait of cancer networks, which is an assumption of our method. Hence, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal or the distribution of topological ranks of genes might be altered. Based on this, we propose a new PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) to detect pathways involved in cancer. We use PageRank to measure the relative topological ranks of genes in each biological pathway, then select hub genes for each pathway, and use Fisher’s exact test to test if the number of hub genes in each pathway is altered from normal to cancer. Alternatively, if the distribution of topological ranks of gene in a pathway is altered between normal and cancer, this pathway might also be involved in cancer. Hence, we use the Kolmogorov–Smirnov test to detect pathways that have an altered distribution of topological ranks of genes between two phenotypes. We apply PoTRA to study hepatocellular carcinoma (HCC) and several subtypes of HCC. Very interestingly, we discover that all significant pathways in HCC are cancer-associated generally, while several significant pathways in subtypes of HCC are HCC subtype-associated specifically. In conclusion, PoTRA is a new approach to explore and discover pathways involved in cancer. PoTRA can be used as a complement to other existing methods to broaden our understanding of the biological mechanisms behind cancer at the system-level.https://peerj.com/articles/4571.pdfPageRankBiological pathwaysPoTRAFisher’s exact testHepatocellular carcinomaKolmogorov–Smirnov test |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chaoxing Li Li Liu Valentin Dinu |
spellingShingle |
Chaoxing Li Li Liu Valentin Dinu Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma PeerJ PageRank Biological pathways PoTRA Fisher’s exact test Hepatocellular carcinoma Kolmogorov–Smirnov test |
author_facet |
Chaoxing Li Li Liu Valentin Dinu |
author_sort |
Chaoxing Li |
title |
Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma |
title_short |
Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma |
title_full |
Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma |
title_fullStr |
Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma |
title_full_unstemmed |
Pathways of topological rank analysis (PoTRA): a novel method to detect pathways involved in hepatocellular carcinoma |
title_sort |
pathways of topological rank analysis (potra): a novel method to detect pathways involved in hepatocellular carcinoma |
publisher |
PeerJ Inc. |
series |
PeerJ |
issn |
2167-8359 |
publishDate |
2018-04-01 |
description |
Complex diseases such as cancer are usually the result of a combination of environmental factors and one or several biological pathways consisting of sets of genes. Each biological pathway exerts its function by delivering signaling through the gene network. Theoretically, a pathway is supposed to have a robust topological structure under normal physiological conditions. However, the pathway’s topological structure could be altered under some pathological condition. It is well known that a normal biological network includes a small number of well-connected hub nodes and a large number of nodes that are non-hubs. In addition, it is reported that the loss of connectivity is a common topological trait of cancer networks, which is an assumption of our method. Hence, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal or the distribution of topological ranks of genes might be altered. Based on this, we propose a new PageRank-based method called Pathways of Topological Rank Analysis (PoTRA) to detect pathways involved in cancer. We use PageRank to measure the relative topological ranks of genes in each biological pathway, then select hub genes for each pathway, and use Fisher’s exact test to test if the number of hub genes in each pathway is altered from normal to cancer. Alternatively, if the distribution of topological ranks of gene in a pathway is altered between normal and cancer, this pathway might also be involved in cancer. Hence, we use the Kolmogorov–Smirnov test to detect pathways that have an altered distribution of topological ranks of genes between two phenotypes. We apply PoTRA to study hepatocellular carcinoma (HCC) and several subtypes of HCC. Very interestingly, we discover that all significant pathways in HCC are cancer-associated generally, while several significant pathways in subtypes of HCC are HCC subtype-associated specifically. In conclusion, PoTRA is a new approach to explore and discover pathways involved in cancer. PoTRA can be used as a complement to other existing methods to broaden our understanding of the biological mechanisms behind cancer at the system-level. |
topic |
PageRank Biological pathways PoTRA Fisher’s exact test Hepatocellular carcinoma Kolmogorov–Smirnov test |
url |
https://peerj.com/articles/4571.pdf |
work_keys_str_mv |
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