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Functional network analysis reveals an immune tolerance mechanism in cancer

Functional network analysis reveals an immune tolerance mechanism in cancer
Functional network analysis reveals an immune tolerance mechanism in cancer
We present a technique to construct a simplification of a feature network which can be used for interactive data exploration, biological hypothesis generation, and the detection of communities or modules of cofunctional features. These are modules of features that are not necessarily correlated, but nevertheless exhibit common function in their network context as measured by similarity of relationships with neighboring features. In the case of genetic networks, traditional pathway analyses tend to assume that, ideally, all genes in a module exhibit very similar function, independent of relationships with other genes. The proposed technique explicitly relaxes this assumption by employing the comparison of relational profiles. For example, two genes which always activate a third gene are grouped together even if they never do so concurrently. They have common, but not identical, function. The comparison is driven by an average of a certain computationally efficient comparison metric between Gaussian mixture models. The method has its basis in the local connection structure of the network and the collection of joint distributions of the data associated with nodal neighborhoods. It is benchmarked on networks with known community structures. As the main application, we analyzed the gene regulatory network in lung adenocarcinoma, finding a cofunctional module of genes including the pregnancy-specific glycoproteins (PSGs). About 20% of patients with lung, breast, uterus, and colon cancer in The Cancer Genome Atlas (TCGA) have an elevated PSG+ signature, with associated poor group prognosis. In conjunction with previous results relating PSGs to tolerance in the immune system, these findings implicate the PSGs in a potential immune tolerance mechanism of cancers.
0027-8424
16339-16345
Belkhatir, Zehor
de90d742-a58f-4425-837c-20ff960fb9b6
Belkhatir, Zehor
de90d742-a58f-4425-837c-20ff960fb9b6

Belkhatir, Zehor (2020) Functional network analysis reveals an immune tolerance mechanism in cancer. Proceedings of the National Academy of Sciences, 117 (28), 16339-16345. (doi:10.1073/pnas.2002179117).

Record type: Article

Abstract

We present a technique to construct a simplification of a feature network which can be used for interactive data exploration, biological hypothesis generation, and the detection of communities or modules of cofunctional features. These are modules of features that are not necessarily correlated, but nevertheless exhibit common function in their network context as measured by similarity of relationships with neighboring features. In the case of genetic networks, traditional pathway analyses tend to assume that, ideally, all genes in a module exhibit very similar function, independent of relationships with other genes. The proposed technique explicitly relaxes this assumption by employing the comparison of relational profiles. For example, two genes which always activate a third gene are grouped together even if they never do so concurrently. They have common, but not identical, function. The comparison is driven by an average of a certain computationally efficient comparison metric between Gaussian mixture models. The method has its basis in the local connection structure of the network and the collection of joint distributions of the data associated with nodal neighborhoods. It is benchmarked on networks with known community structures. As the main application, we analyzed the gene regulatory network in lung adenocarcinoma, finding a cofunctional module of genes including the pregnancy-specific glycoproteins (PSGs). About 20% of patients with lung, breast, uterus, and colon cancer in The Cancer Genome Atlas (TCGA) have an elevated PSG+ signature, with associated poor group prognosis. In conjunction with previous results relating PSGs to tolerance in the immune system, these findings implicate the PSGs in a potential immune tolerance mechanism of cancers.

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Published date: 29 June 2020

Identifiers

Local EPrints ID: 501101
URI: http://eprints.soton.ac.uk/id/eprint/501101
ISSN: 0027-8424
PURE UUID: e8725d47-0258-4874-9e6e-b9f941d921fe
ORCID for Zehor Belkhatir: ORCID iD orcid.org/0000-0001-7277-3895

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Date deposited: 23 May 2025 16:49
Last modified: 25 May 2025 05:21

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Author: Zehor Belkhatir ORCID iD

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