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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.

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.

SUBMITTER: Flowers E

PROVIDER: S-EPMC6700896 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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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.

Flowers Elena E Flentje Annesa A Levine Jon J Olshen Adam A Hammer Marilyn M Paul Steven S Conley Yvette Y Miaskowski Christine C Kober Kord M KM

Biological research for nursing 20190131 2

<h4>Context</h4>Fatigue is the most common symptom associated with cancer and its treatment. Investigation of molecular mechanisms associated with fatigue may identify new therapeutic targets.<h4>Objective</h4>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.<h4>Methods</h4>Latent class analysis (LCA) was used to identify evening fatigue phenotypes. ...[more]

PMID: 30701989

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Project description:Fatigue, a highly prevalent and distressing symptom during chemotherapy (CTX), demonstrates diurnal and interindividual variability in severity. Little is known about the associations between variations in genes involved in inflammatory processes and morning and evening fatigue severity during CTX. The purposes of this study, in a sample of oncology patients (N=543) with breast, gastrointestinal (GI), gynecological (GYN), or lung cancer who received two cycles of CTX, were to determine whether variations in genes involved in inflammatory processes were associated with inter-individual variability in initial levels as well as in the trajectories of morning and evening fatigue. Patients completed the Lee Fatigue Scale to determine morning and evening fatigue severity a total of six times over two cycles of CTX. Using a whole exome array, 309 single nucleotide polymorphisms SNPs among the 64 candidate genes that passed all quality control filters were evaluated using hierarchical linear modeling (HLM). Based on the results of the HLM analyses, the final SNPs were evaluated for their potential impact on protein function using two bioinformational tools. The following inflammatory pathways were represented: chemokines (3 genes); cytokines (12 genes); inflammasome (11 genes); Janus kinase/signal transducers and activators of transcription (JAK/STAT, 10 genes); mitogen-activated protein kinase/jun amino-terminal kinases (MAPK/JNK, 3 genes); nuclear factor-kappa beta (NFkB, 18 genes); and NFkB and MAP/JNK (7 genes). After controlling for self-reported and genomic estimates of race and ethnicity, polymorphisms in six genes from the cytokine (2 genes); inflammasome (2 genes); and NFkB (2 genes) pathways were associated with both morning and evening fatigue. Polymorphisms in six genes from the inflammasome (1 gene); JAK/STAT (1 gene); and NFkB (4 genes) pathways were associated with only morning fatigue. Polymorphisms in three genes from the inflammasome (2 genes) and the NFkB (1 gene) pathways were associated with only evening fatigue. Taken together, these findings add to the growing body of evidence that suggests that morning and evening fatigue are distinct symptoms.

Dataset Information

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.

Publications

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.

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