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. 2019 Jan-Dec:15:1744806919878088.
doi: 10.1177/1744806919878088.

Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology in breast cancer survivors with chronic paclitaxel-induced peripheral neuropathy

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Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology in breast cancer survivors with chronic paclitaxel-induced peripheral neuropathy

Kord M Kober et al. Mol Pain. 2019 Jan-Dec.

Abstract

Background: The major dose-limiting toxicity of paclitaxel, one of the most commonly used drugs to treat breast cancer, is peripheral neuropathy (paclitaxel-induced peripheral neuropathy). Paclitaxel-induced peripheral neuropathy, which persists into survivorship, has a negative impact on patient’s mood, functional status, and quality of life. Currently, no interventions are available to treat paclitaxel-induced peripheral neuropathy. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie paclitaxel-induced peripheral neuropathy. While data from preclinical studies suggest that disrupting cytoskeleton- and axon morphology-related processes are a potential mechanism for paclitaxel-induced peripheral neuropathy, clinical evidence is limited. The purpose of this study in breast cancer survivors was to evaluate whether differential gene expression and co-expression patterns in these pathways are associated with paclitaxel-induced peripheral neuropathy.

Methods: Signaling pathways and gene co-expression modules associated with cytoskeleton and axon morphology were identified between survivors who received paclitaxel and did (n = 25) or did not (n = 25) develop paclitaxel-induced peripheral neuropathy.

Results: Pathway impact analysis identified four significantly perturbed cytoskeleton- and axon morphology-related signaling pathways. Weighted gene co-expression network analysis identified three co-expression modules. One module was associated with paclitaxel-induced peripheral neuropathy group membership. Functional analysis found that this module was associated with four signaling pathways and two ontology annotations related to cytoskeleton and axon morphology.

Conclusions: This study, which is the first to apply systems biology approaches using circulating whole blood RNA-seq data in a sample of breast cancer survivors with and without chronic paclitaxel-induced peripheral neuropathy, provides molecular evidence that cytoskeleton- and axon morphology-related mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors and suggests pathways and a module of genes for validation and as potential therapeutic targets.

Keywords: Chemotherapy; axon morphology; breast cancer; cytoskeleton; gene co-expression network analysis; gene expression; paclitaxel; pathway impact analysis; peripheral neuropathy; signaling pathway; survivor.

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Figures

Figure 1.
Figure 1.
An overview of the two analytic approaches used to evaluate for cytoskeleton- and axon morphology-related gene (G) expression patterns associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors (S) with (C) and without (N) PIPN: [1] PIA and [2] WGCNA. The KEGG pathways and Gene Ontology categories were evaluated for cytoskeleton and axon-morphology biological processes. DGE: differential gene expression; KEGG: Kyoto Encyclopedia of Genes and Genomes; MLR: multiple logistic regression; PIA: pathway impact analysis; PPI: protein–protein interaction; WGCNA: weighted gene co-expression network analysis.
Figure 2.
Figure 2.
Cluster dendrogram and module colors showing the module assignments for the gene co-expression data. The color rows underneath the cluster dendrogram show the module assignment from the unmerged Dynamic Tree Cut method and the final module set from the Merged dynamic method.
Figure 3.
Figure 3.
STRING connectivity network demonstrating a protein–protein interaction network of predicted functional partners for differentially expressed genes in the brown module. Nodes represent all proteins produced by a single protein coding gene locus. Edges represent specific or meaningful associations. Node color: axon guidance pathway (KEGG hsa04360) genes (red), second shell of interactors (white). Node size: protein of unknown three-dimensional (3D) structure (small), protein of known or predicted 3D structure (large). Color of the edges connecting the nodes represents the types of evidence supporting the connections: predicted gene neighborhood (green), predicted gene fusions (red), known interactions from experimental evidence (pink), co-expression (black), and text-mining (green). Disconnected nodes in the network are not displayed.

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References

    1. Banach M, Juranek JK, Zygulska AL. Chemotherapy-induced neuropathies-a growing problem for patients and health care providers. Brain Behav 2017; 7: e00558. - PMC - PubMed
    1. Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in cancer survivors: an underdiagnosed clinical entity? Am Soc Clin Oncol Educ Book 2015; 35: e553–e560. - PubMed
    1. Denlinger CS, Ligibel JA, Are M, Baker KS, Demark-Wahnefried W, Dizon D, Friedman DL, Goldman M, Jones L, King A, Ku GH, Kvale E, Langbaum TS, Leonardi-Warren K, McCabe MS, Melisko M, Montoya JG, Mooney K, Morgan MA, Moslehi JJ, O’Connor T, Overholser L, Paskett ED, Peppercorn J, Raza M, Rodriguez MA, Syrjala KL, Urba SG, Wakabayashi MT, Zee P, McMillian NR, Freedman-Cass DA. Survivorship: screening for cancer and treatment effects, version 2.2014. J Natl Compr Canc Netw 2014; 12: 1526–1531. - PMC - PubMed
    1. Kvale E, Urba SG. NCCN guidelines for survivorship expanded to address two common conditions. J Natl Compr Canc Netw 2014; 12: 825–827. - PubMed
    1. Mols F, Beijers T, Vreugdenhil G, van de Poll-Franse L. Chemotherapy-induced peripheral neuropathy and its association with quality of life: a systematic review. Support Care Cancer 2014; 22: 2261–2269. - PubMed

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