Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year

ABSTRACT The biological basis underlying cognitive dysfunction in women with early-stage breast cancer (BC) remains unclear, but could reflect gene expression changes that arise from the acquisition and long-term retention of soma-wide alterations in DNA methylation in response to chemotherapy. In this longitudinal study, we identified differences in peripheral methylation patterns present in women prior to treatment (T1) and 1 year after receiving chemotherapy (T4) and evaluated relationships among the differential methylation (DM) ratios with changes in cognitive function. A total of 58 paired (T1 and T4) blood specimens were evaluated. Methylation values were determined for DNA isolated from whole blood using a genome-wide array . Cognitive function was measured using the validated, computerized CNS Vital Signs platform. Relationships between methylation patterns and cognitive domain scores were compared using a stepwise linear regression analysis, with demographic variables as covariates. The symptom comparison analysis was restricted to 2,199 CpG positions showing significant methylation ratio changes between T1 and T4. The positions with DM were enriched for genes involved in the modulation of cytokine concentrations. Significant DM ratios were associated with memory domain (56 CpGs). Eight of the ten largest DM ratio changes associated with lack of memory improvement were localized to genes involved in either neural function (ECE2, PPFIBP2) or signalling processes (USP6NL, RIPOR2, KLF5, UBE2V1, DGKA, RPS6KA1). These results suggest that epigenetic changes acquired and retained for at least one year in non-tumour cells following chemotherapy may be associated with a lack of memory improvement following treatment in BC survivors.

[1]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[2]  David R. Anderson,et al.  Model selection and multimodel inference : a practical information-theoretic approach , 2003 .

[3]  F. Balkwill.  Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[4]  C. Gualtieri,et al.  Reliability and validity of a computerized neurocognitive test battery, CNS Vital Signs. , 2006, Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists.

[5]  A. Lustig,et al.  Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues. , 2007, Experimental cell research.

[6]  M. Blasco,et al.  Cellular Senescence in Cancer and Aging , 2007, Cell.

[7]  R. Rodriguiz,et al.  Animals lacking endothelin‐converting enzyme‐2 are deficient in learning and memory , 2008, Genes, brain, and behavior.

[8]  Arturas Petronis,et al.  Epigenetic approaches to psychiatric disorders , 2010, Dialogues in clinical neuroscience.

[9]  In Ah Kim,et al.  Promoter CpG island hypermethylation during breast cancer progression , 2010, Virchows Archiv.

[10]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[11]  M. Maze,et al.  The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction , 2010, Critical care.

[12]  Andra M. Smith,et al.  Pre-Chemotherapy Differences in Visuospatial Working Memory in Breast Cancer Patients Compared to Controls: An fMRI Study , 2011, Front. Hum. Neurosci..

[13]  C. Heckler,et al.  Differential expression of cytokines in breast cancer patients receiving different chemotherapies: implications for cognitive impairment research , 2012, Supportive Care in Cancer.

[14]  Yuan Qi,et al.  Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer. , 2011, Journal of the National Cancer Institute.

[15]  P. Allavena,et al.  Chemokines in cancer related inflammation. , 2011, Experimental Cell Research.

[16]  J. Day,et al.  Epigenetic mechanisms in memory and synaptic function. , 2011, Epigenomics.

[17]  J. Eddy,et al.  Epigenetic patterns associated with the immune dysregulation that accompanies psychosocial distress , 2011, Brain, Behavior, and Immunity.

[18]  Brian J. Stevenson,et al.  Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. , 2012, Genome research.

[19]  M. Gallagher,et al.  Characterization of CpG island DNA methylation of impairment-related genes in a rat model of cognitive aging , 2012, Epigenetics.

[20]  Andrew J. Saykin,et al.  Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage , 2012, Breast Cancer Research and Treatment.

[21]  J. Myers.  Chemotherapy-related cognitive impairment: the breast cancer experience. , 2012, Oncology nursing forum.

[22]  M. Feuerstein,et al.  Cognitive limitations associated with tamoxifen and aromatase inhibitors in employed breast cancer survivors , 2012, Psycho-oncology.

[23]  Devin C. Koestler,et al.  DNA methylation arrays as surrogate measures of cell mixture distribution , 2012, BMC Bioinformatics.

[24]  M. Irwin,et al.  The association between pro-inflammatory cytokines, regional cerebral metabolism, and cognitive complaints following adjuvant chemotherapy for breast cancer , 2013, Brain Imaging and Behavior.

[25]  C. Eckman,et al.  Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[26]  K. Conneely,et al.  Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy , 2014, Brain, Behavior, and Immunity.

[27]  A. Starkweather,et al.  Potential Epigenetic Mechanism(s) Associated With the Persistence of Psychoneurological Symptoms in Women Receiving Chemotherapy for Breast Cancer , 2014, Biological research for nursing.

[28]  P. Eline Slagboom,et al.  MethylAid: visual and interactive quality control of large Illumina 450k datasets , 2014, Bioinform..

[29]  C. Cheung,et al.  Chemobrain: a critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. , 2015, Cytokine.

[30]  H. Bear,et al.  Perceived Stress Levels, Chemotherapy, Radiation Treatment and Tumor Characteristics Are Associated with a Persistent Increased Frequency of Somatic Chromosomal Instability in Women Diagnosed with Breast Cancer: A One Year Longitudinal Study , 2015, PloS one.

[31]  James Paul,et al.  Platinum-Based Chemotherapy Induces Methylation Changes in Blood DNA Associated with Overall Survival in Patients with Ovarian Cancer , 2016, Clinical Cancer Research.

[32]  M. Ringnér,et al.  An integrated genomics analysis of epigenetic subtypes in human breast tumors links DNA methylation patterns to chromatin states in normal mammary cells , 2016, Breast Cancer Research.

[33]  A. Jemal,et al.  Cancer treatment and survivorship statistics, 2016 , 2016, CA: a cancer journal for clinicians.

[34]  T. P. Centeno,et al.  DNA methylation changes in plasticity genes accompany the formation and maintenance of memory , 2015, Nature Neuroscience.

[35]  A. Starkweather,et al.  Relationships among psychoneurological symptoms and levels of C-reactive protein over 2 years in women with early-stage breast cancer , 2016, Supportive Care in Cancer.

[36]  Maxime W. C. Rousseaux,et al.  Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model , 2016, Neuron.

[37]  A. Starkweather,et al.  Relationship of systemic cytokine concentrations to cognitive function over two years in women with early stage breast cancer , 2016, Journal of Neuroimmunology.

[38]  S. Yi,et al.  Evolutionary Transition of Promoter and Gene Body DNA Methylation across Invertebrate–Vertebrate Boundary , 2015, Molecular biology and evolution.

[39]  R. Frisina,et al.  Comprehensive Audiometric Analysis of Hearing Impairment and Tinnitus After Cisplatin-Based Chemotherapy in Survivors of Adult-Onset Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  C. Eckman,et al.  Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex , 2016, Neurobiology of Aging.

[41]  J. David Sweatt,et al.  Neural plasticity and behavior – sixty years of conceptual advances , 2016, Journal of neurochemistry.

[42]  J. Hardy,et al.  The amyloid hypothesis of Alzheimer's disease at 25 years , 2016, EMBO molecular medicine.

[43]  J. Levine,et al.  Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery , 2017, Cytokine.

[44]  D. Spengler,et al.  Epigenomics of Major Depressive Disorders and Schizophrenia: Early Life Decides , 2017, International journal of molecular sciences.

[45]  S. Sereika,et al.  Cognitive functioning and quality of life following chemotherapy in pre- and peri-menopausal women with breast cancer , 2018, Supportive Care in Cancer.

[46]  C. Cunningham,et al.  Systemic TNF-α produces acute cognitive dysfunction and exaggerated sickness behavior when superimposed upon progressive neurodegeneration , 2017, Brain, Behavior, and Immunity.

[47]  S. Schwartz,et al.  Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance , 2017, PloS one.

[48]  M. Joëls,et al.  Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment , 2017, Translational Psychiatry.

[49]  B. Morland,et al.  Sodium Thiosulfate for Protection from Cisplatin‐Induced Hearing Loss , 2018, The New England journal of medicine.

[50]  Andrew P Feinberg,et al.  The Key Role of Epigenetics in Human Disease Prevention and Mitigation. , 2018, The New England journal of medicine.

[51]  Hongbo Liu,et al.  Specific breast cancer prognosis‐subtype distinctions based on DNA methylation patterns , 2018, Molecular oncology.

[52]  R. K. Galimudi,et al.  Collagenase-1 (-1607 1G/2G), Gelatinase-A (-1306 C/T), Stromelysin-1 (-1171 5A/6A) functional promoter polymorphisms in risk prediction of type 2 diabetic nephropathy. , 2018, Gene.

[53]  O. Kovalchuk,et al.  Adverse effects of paternal chemotherapy exposure on the progeny brain: intergenerational chemobrain , 2018, Oncotarget.

[54]  S. Sajikumar,et al.  Epigenetics and memory: Emerging role of histone lysine methyltransferase G9a/GLP complex as bidirectional regulator of synaptic plasticity , 2019, Neurobiology of Learning and Memory.

[55]  A. Olshen,et al.  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 , 2019, Biological research for nursing.

[56]  J. Potash,et al.  Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals , 2019, Translational Psychiatry.