A Pilot Study Using a Multistaged Integrated Analysis of Gene Expression and Methylation to Evaluate Mechanisms for Evening Fatigue in Women Who Received Chemotherapy for Breast Cancer

Author:

Flowers Elena1,Flentje Annesa1,Levine Jon2,Olshen Adam2,Hammer Marilyn3,Paul Steven1,Conley Yvette4,Miaskowski Christine1,Kober Kord M.1

Affiliation:

1. School of Nursing, University of California, San Francisco, San Francisco, CA, USA

2. School of Medicine, University of California, San Francisco, San Francisco, CA, USA

3. Department of Nursing, Mount Sinai Hospital, New York, NY, USA

4. School of Nursing, University of Pittsburg, Pittsburg, PA, USA

Abstract

Context: Fatigue is the most common symptom associated with cancer and its treatment. Investigation of molecular mechanisms associated with fatigue may identify new therapeutic targets. Objective: The objective of this pilot study was to evaluate the relationships between gene expression and methylation status and evening fatigue severity in women with breast cancer who received chemotherapy. Methods: Latent class analysis (LCA) was used to identify evening fatigue phenotypes. In this analysis, the lowest (i.e., moderate, n = 7) and highest (i.e., very high, n = 29) fatigue-severity classes identified using LCA were analyzed via two stages. First, a total of 32,609 transcripts from whole blood were evaluated for differences in expression levels between the classes. Next, 637 methylation sites located within the putative transcription factor binding sites for those genes demonstrating differential expression were evaluated for differential methylation state between the classes. Results: A total of 89 transcripts in 75 unique genes were differentially expressed between the moderate (the lowest fatigue-severity class identified) and very high evening fatigue classes. In addition, 23 differentially methylated probes and three differentially methylated regions were found between the moderate and very high evening fatigue classes. Conclusions: Using a multistaged integrated analysis of gene expression and methylation, differential methylation was identified in the regulatory regions of genes associated with previously hypothesized mechanisms for fatigue, including inflammation, immune function, neurotransmission, circadian rhythm, skeletal muscle energy, carbohydrate metabolism, and renal function as well as core biological processes including gene transcription and the cell-cycle regulation.

Publisher

SAGE Publications

Subject

Research and Theory

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