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. 2023 Mar;12(6):7369-7380.
doi: 10.1002/cam4.5435. Epub 2022 Nov 14.

Perturbations in common and distinct inflammatory pathways associated with morning and evening fatigue in outpatients receiving chemotherapy

Kord M Kober  1   2 , Carolyn Harris  1 , Yvette P Conley  3 , Anand Dhruva  4 , Vasuda Dokiparthi  1 , Marilyn J Hammer  5 , Jon D Levine  4 , Kate Oppegaard  1 , Steven Paul  1 , Joosun Shin  1 , Anatol Sucher  1 , Fay Wright  6 , Brian Yuen  1 , Adam B Olshen  2   3 , Christine Miaskowski  1   2   4
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Perturbations in common and distinct inflammatory pathways associated with morning and evening fatigue in outpatients receiving chemotherapy

Kord M Kober et al. Cancer Med. 2023 Mar.

Abstract

Background: Moderate to severe fatigue occurs in up to 94% of patients with cancer. Recent evidence suggests that morning and evening fatigue are distinct dimensions of physical fatigue. The purposes of this study were to evaluate the transcriptome for common and distinct perturbed inflammatory pathways in patients receiving chemotherapy who reported low versus high levels of morning or low versus high levels of evening cancer-related fatigue.

Methods: Patients completed questionnaires during the week prior to their chemotherapy treatment. Severity of morning and evening fatigue was evaluated using the Lee Fatigue Scale. Gene expression and pathway impact analyses (PIA) were performed in two independent samples using RNA-sequencing (n = 357) and microarray (n = 360). Patterns of interactions between and among these perturbed pathways were evaluated using a knowledge network (KN).

Results: Across the PIA, nine perturbed pathways (FDR < 0.025) were common to both morning and evening fatigue, six were distinct for morning fatigue, and four were distinct for evening fatigue. KN (19 nodes, 39 edges) identified the phosphatidylinositol 3-kinase (PI3K)-Akt pathway node (perturbed in evening fatigue) with the highest betweenness (0.255) and closeness (0.255) centrality indices. The next highest betweenness centrality indices were seen in pathways perturbed in evening fatigue (i.e., nuclear factor kappa B: 0.200, natural killer cell-mediated cytotoxicity: 0.178, mitogen-activated protein kinase: 0.175).

Conclusions: This study describes perturbations in common and distinct inflammatory pathways associated with morning and/or evening fatigue. PI3K-Akt was identified as a bottleneck pathway. The analysis identified potential targets for therapeutic interventions for this common and devastating clinical problem.

Keywords: cancer; chemotherapy; cytokines; fatigue; gene expression; inflammation; knowledge network; pathway impact analysis.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
A knowledge network generated from connections among the common and distinct perturbed inflammation‐related KEGG signaling pathways associated with morning and evening cancer‐related fatigue. Nodes represent each of the KEGG signaling pathways. Edges represent connections between the pathways. Edge labels identify a shared member of the network. Edges between pathways unique to morning and evening fatigue are colored purple.
See this image and copyright information in PMC

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