Defining the role of aneuploidy throughout tumorigenesis
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021
| Váldodahkki: | |
|---|---|
| Eará dahkkit: | |
| Materiálatiipa: | Oahppočájánas |
| Giella: | eng |
| Almmustuhtton: |
Massachusetts Institute of Technology
2021
|
| Fáttát: | |
| Liŋkkat: | https://hdl.handle.net/1721.1/130665 |
| _version_ | 1826208308945485824 |
|---|---|
| author | Silberman, Rebecca Estelle. |
| author2 | Angelika Amon. |
| author_facet | Angelika Amon. Silberman, Rebecca Estelle. |
| author_sort | Silberman, Rebecca Estelle. |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021 |
| first_indexed | 2024-09-23T14:03:46Z |
| format | Thesis |
| id | mit-1721.1/130665 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T14:03:46Z |
| publishDate | 2021 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1306652021-05-25T03:17:33Z Defining the role of aneuploidy throughout tumorigenesis Silberman, Rebecca Estelle. Angelika Amon. Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology Biology. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021 Cataloged from the official PDF of thesis. Includes bibliographical references. Aneuploidy is a state of genome imbalance which alters the copy number of whole chromosomes. While aneuploidy is rare in healthy tissues, it is one of the most common features of cancerous tumors. Studies of aneuploid yeast and aneuploid mammalian cells growing in culture revealed that aneuploidy induces cellular stress and slows proliferation. So it is surprising that aneuploidy is a hallmark of cancer, a disease of cellular over-proliferation and inappropriate cell survival. We sought to elucidate aneuploidy's role in tumorigenesis by defining the factors that affect the prevalence of aneuploid cells in normal, pre-cancerous, and cancerous tissues. First, we investigated whether aneuploid mammalian cells experience fitness defects in vivo. We found that aneuploidy decreases hematopoietic stem cells' fitness and that aneuploid cells are selected against in normal, regenerating tissues in vivo. However, we also found that aneuploid cells can accumulate in the hematopoietic system when purifying selection is relaxed following bone marrow reconstitution. We then sought to extend our observations to the context of pre-cancerous tissues. We analyzed the prevalence of aneuploidy in the highly tumorigenic, but histologically normal tissues of women harboring heterozygous germline BRCA2 mutations. Using single-cell sequencing, we revealed that breast cells from BRCA2 mutation carriers lack aneuploidy but feature a distinct form of genome imbalance called sub-chromosomal copy number variants (CNVs), even before the initiation of tumorigenesis. We then analyzed the timing with which these two forms of genome imbalance--whole-chromosomal aneuploidy and sub-chromosomal CNVs--arise during tumorigenesis. We found that CNVs are present in the cells of early precursors of multiple cancers, but that whole-chromosomal aneuploidy arises late in tumorigenesis. Our findings propose that whole-chromosomal aneuploidy reduces cells' fitness in both normal and pre-cancerous tissues, and that aneuploidy is selected against throughout tumorigenesis. This has implications for the role of aneuploidy in cancer, suggesting that aneuploidy does not contribute to early tumorigenesis. by Rebecca Estelle Silberman. Ph. D. Ph.D. Massachusetts Institute of Technology, Department of Biology 2021-05-24T19:39:43Z 2021-05-24T19:39:43Z 2021 2021 Thesis https://hdl.handle.net/1721.1/130665 1251767363 eng MIT theses may be protected by copyright. Please reuse MIT thesis content according to the MIT Libraries Permissions Policy, which is available through the URL provided. http://dspace.mit.edu/handle/1721.1/7582 233 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Silberman, Rebecca Estelle. Defining the role of aneuploidy throughout tumorigenesis |
| title | Defining the role of aneuploidy throughout tumorigenesis |
| title_full | Defining the role of aneuploidy throughout tumorigenesis |
| title_fullStr | Defining the role of aneuploidy throughout tumorigenesis |
| title_full_unstemmed | Defining the role of aneuploidy throughout tumorigenesis |
| title_short | Defining the role of aneuploidy throughout tumorigenesis |
| title_sort | defining the role of aneuploidy throughout tumorigenesis |
| topic | Biology. |
| url | https://hdl.handle.net/1721.1/130665 |
| work_keys_str_mv | AT silbermanrebeccaestelle definingtheroleofaneuploidythroughouttumorigenesis |