Show simple item record

dc.contributor.authorTrigos Gomez, Anna Sofia
dc.date.accessioned2018-12-05T22:17:30Z
dc.date.available2018-12-05T22:17:30Z
dc.date.issued2018en_US
dc.identifier.urihttp://hdl.handle.net/11343/219211
dc.description© 2018 Dr. Anna Sofia Trigos Gomez
dc.description.abstractAll biological systems follow the rules and constraints imposed during their evolution. Current-day gene phenotypes such as gene expression, gene essentiality, gene function and protein localization are linked with the time of evolutionary emergence of genes. In cancer, tumours rely on cellular processes that date back to unicellular ancestors (e.g., cell replication, glycolysis), while dysregulating key pathways linked to the emergence of multicellularity, suggesting that the transition from unicellularity to multicellularity left vulnerabilities in cells that act as guiding principles during cancer development. Therefore, in this thesis I integrate genomics, systems biology and evolutionary biology to investigate fundamental principles of tumourigenesis related to the evolutionary history of genes using gene expression and somatic mutation information across multiple tumour types. First, I coupled the evolutionary age of genes and cellular processes with their expression levels in tumour and normal samples, and found that tumours consistently activate genes from unicellular ancestors while switching off genes related to multicellularity. These consistent patterns were supported by a mutual exclusivity between the activity of genes and transcriptional networks of unicellular and multicellular ancestors, which promoted convergent evolution towards a state of loss of multicellularity. Second, I investigated how somatic mutations disrupted gene regulatory networks. Genes that emerged together with early metazoans were enriched in point mutations and copy- number alterations, indicating that gene innovations that took place at the onset of multicellularity play a fundamental role in cancer development. Importantly, the uncoupling of regulatory networks of unicellular and multicellular ancestors was mostly due to point mutations in gene regulators linking these networks. On the other hand, copy-number aberrations were directly involved in the activation and inactivation of unicellular and multicellular genes, suggesting point mutations and copy-number aberrations play complementary roles in the loss of regulation between unicellular and multicellular transcriptional networks in cancer. Third, I focused on novel transcriptional associations formed during tumourigenesis using gene co-expression module analysis. Significant levels of rewiring between unicellular and multicellular genes were found across tumours. This rewiring was mostly driven by gene amplifications, which promoted the formation of tumour-specific modules composed of novel transcriptional associations between unicellular and multicellular genes, once more linking the genes and regulatory associations evolved at the onset of multicellularity to cancer development. The findings of this work reveal fundamental principles driving cancer development associated with genes and transcriptional networks evolved during the transition from unicellularity to multicellularity. I propose a model whereby activation of programs that date back to unicellular ancestors and the deactivation of multicellular programs is driven by an inherent mutual exclusivity of these genes together with the breakage of regulation between unicellular and multicellular genes by point mutations, whereas the formation of novel transcriptional associations between these genes in tumours is driven by copy-number changes. Finally, I identify potential novel drivers based on their key role in uncoupling unicellular and multicellular transcriptional networks across tumours and suggest novel treatment strategies derived from this evolutionary approach. The results presented in this thesis contribute to our understanding of how past evolutionary events led to vulnerabilities in transcriptional networks that influence cancer development, and highlight the benefits of the integration of evolutionary concepts with genomics and network biology to identify fundamental principles of cancer.en_US
dc.rightsTerms and Conditions: Copyright in works deposited in Minerva Access is retained by the copyright owner. The work may not be altered without permission from the copyright owner. Readers may only download, print and save electronic copies of whole works for their own personal non-commercial use. Any use that exceeds these limits requires permission from the copyright owner. Attribution is essential when quoting or paraphrasing from these works.
dc.subjectcanceren_US
dc.subjectevolutionen_US
dc.subjectmulticellularityen_US
dc.subjectnetworksen_US
dc.subjectgenomicsen_US
dc.subjectbioinformaticsen_US
dc.subjecttranscriptomicsen_US
dc.titleThe evolutionary history of genes and transcriptional networks reveals fundamental properties of cancer associated with the breakdown of multicellularityen_US
dc.typePhD thesisen_US
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
dc.identifier.orcid0000-0002-5915-2952en_US
melbourne.thesis.supervisornameGoode, David
melbourne.thesis.supervisoremailDavid.Goode@petermac.orgen_US
melbourne.contributor.authorTrigos Gomez, Anna Sofia
melbourne.accessrightsOpen Access


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record