Aneuploidy in the human brain and cancer: Studying heterogeneity using single-cell sequencing

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    When a cell does not have the normal chromosome content with for each chromosome a copy from each parent it is called aneuploid. Aneuploidy can be studied using various methods. In this thesis an overview is presented of the different technologies that are widely used to detect aneuploidy. Large numbers of aneuploid cells have been identified in developing and adult mouse brain using fluorescence in situ hybridization (FISH). Shortly thereafter, the presence of aneuploid cells was confirmed in human brain and reported to be even higher in neurodegenerative diseases. In contrast, various single cell sequencing studies did not show any, or much lower levels of, aneuploidy. In this thesis we discuss the possible role of aneuploidy in normal brain development and neurodegeneration, and set out to provide more insight into the presence or absence of aneuploid cells in the human brain using single cell sequencing. We sequenced brain cells from individuals with no brain disease and brain cells from patients with different stages of Alzheimer’s disease. We found low levels of aneuploidy, both in normal and diseased brain, with no increase in Alzheimer’s disease. Our results show that it is unlikely that aneuploidy has an important role in the (dys)function of normal human brain or in the development or progression of Alzheimer’s disease.
    Although we did not find evidence for aneuploidy to be common in the brain, aneuploidy is a known hallmark of cancer. The great majority of cancers is aneuploid. The heterogeneity of a tumor can be studied using single cell sequencing. This can reveal the mutational or aneuploidy and copy number aberration patterns of individual cells. We review studies using single cell sequencing on primary tumors, metastases and circulating tumor cells, and discuss how single cell sequencing can and will contribute to the diagnosis, prognosis and monitoring of cancer.
    Also, we sequenced large numbers of individual cells from a patient with small cell lung cancer. Analysis of tumor cells isolated from two sites of the primary tumor as well as metastases in the liver, adrenal gland and lymph node revealed both monoclonal and polyclonal metastatic seeding patterns. Moreover, we show that the patterns of copy number aberrations and the level of heterogeneity varies between the different sites.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    • Lansdorp, Peter, Supervisor
    • Foijer, Floris, Co-supervisor
    • Spierings, Diana, Co-supervisor
    Award date23-Oct-2017
    Place of Publication[Groningen]
    Print ISBNs978-94-034-0136-2
    Electronic ISBNs978-94-034-0135-5
    Publication statusPublished - 2017

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