Leveraging technological opportunities in cancer genomics

Abstract

Cancer genomics is a thriving field with constant methodological and technological advances. These developments enable personalized and targeted treatments for cancer patients based on the unique genomic profiles of tumors. In this thesis I leveraged novel technologies for the advancement of cancer research and care. In chapter 1 I introduced the different types of genomic variation, the genomic characteristics of cancer, the importance of genomic technology for personalized medicine and the potential of liquid biopsies for low-invasive cancer monitoring. I also introduced model systems used in cancer research, including patient-derived organoids (PDOs), detailing the potential for their use particularly in ovarian cancer (OC). Lastly, I introduced the role of somatic SV in cancer and the different sequencing technologies that are used to detect them, along with the challenges that this presents.

In the first part of this thesis, we used organoid technology to advance OC research. In chapter 2 we established and characterized a PDO biobank that faithfully represented the disease, and presented its applications. Next, we expanded the OC-PDO biobank and used those PDOs for extensive drug screening in chapter 3. We performed screening assays on 36 PDO lines derived from 23 patients and retrospectively compared their drug responses to clinical responses of the patients. In the second part of the thesis I focused on somatic structural variation in cancer. Accurate detection of structural variants (SVs) is still challenging, and truth sets and standardized workflows are lacking. We tackled the challenge of accurate somatic SV detection in cancer genomes and generated a truth set of somatic SVs that can be used for method development and benchmarking, which I presented in chapter 4. Furthermore, we developed methods to utilize long-read sequencing and somatic structural variants (SVs) for cancer dynamics after treatment and minimal residual disease tracing. In chapter 5, we developed an assay that leveraged nanopore sequencing technology for rapid detection of somatic SVs from a tumor.We also developed an assay that leverages CRISPR-Cas9 based enrichment of genomic targets in pediatric leukemias from the lymphoid lineage. In chapter 6, we targeted loci recurrently involved in genomic rearrangements in these leukemias, such as the immunoglobulin (Ig) and T-cell receptor (TCR) loci, and the KMT2A and SIL-TAL1 fusion-gene loci. Finally, in chapter 7 I discussed and reflected on the technological advances presented in the previous chapters. I explained the advantages of PDO technology in OC research, but also the challenges for its further clinical implementation in clinical care. Similarly, I identify current challenges and propose several solutions for enhancing the knowledge of the role of somatic SVs in cancer and implementation of long-read sequencing. In conclusion, this thesis proposes several cancer genomics technological opportunities to advance cancer research and develop personalized diagnostic assays to improve patients’ outcomes.