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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Acquired epigenetic and chromosomal changes in women treated for breast cancer

Aboalela, Noran 01 January 2014 (has links)
Improved survival for women receiving chemotherapy for breast cancer (BC) has been accompanied by the development/persistence of psychoneurological symptoms (PNS) that compromise their quality of life. The biological basis for these PNS is unknown, but could reflect the acquisition of soma-wide chromosomal/epigenetic alterations. An important first step in testing this hypothesis is to determine if somatic genetic/epigenetic changes arise and persist following treatment. To answer this question we longitudinally studied 71 women (ages 23-71) with early-stage BC and collected measures before chemotherapy (baseline), and 4 weeks (mid-chemo); six months (during radiation therapy for a subset of women); and one year following the initiation of chemotherapy. Acquired lymphocyte chromosomal instability (scored by micronuclei frequencies [MNF]) showed a significant increase in post-treatment compared to baseline time-points (p<0.0001), with these increases persisting for at least one year following chemotherapy. Significant predictive associations were observed between MNF and tumor characteristics [luminal B (lower MNF; p=0.0182); triple negative (higher MNF; p=0.0446)], radiotherapy (higher MNF; p=0.0004), the type of chemotherapy received (p=0.0463), race (Caucasians > African Americans; p=0.0037), perceived stress levels (positive-association; p=0.0123), and cognitive flexibility domain measures (positive-association; p=0.0238). Genome-wide acquired methylation changes were also measured in peripheral blood cells, with 1265 sites showing significant differential methylation following chemotherapy. These sites were localized to open sea, shores, shelves, and CpG island sequences and included sites within genes involved in cell cycle, DNA repair, transcription regulation, signal transduction pathways, neuronal regeneration, and immunity. To determine if the genetic/epigenetic alterations acquired in peripheral blood cells correlated with those in tumor cells, BC tumors from 10 participants were analyzed using a genome-wide copy number/targeted mutations (CN/M) microarray. While no clear blood-tumor cell correlations were detected, genome-wide CN/M evaluations showed promise for stratifying tumors. Lastly, in an unrelated project studying a rare case of fetuses in fetu, methylation changes acquired in embryogenesis were shown to be influenced by both environmental and genetic cues. In summary, acquired chromosomal/epigenetic alterations do arise following chemotherapy (and in embryogenesis). Further delineation of these acquired changes could increase our understanding of the biological basis for cancer-related side-effects and help to identify “at risk” individuals.

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