Evaluations and Consequences of Tumour Evolution

Somatic mutations detected in cancer genomes are the result of mutation accumulation since the fertilized egg. Select mutations, as the result of mutagenic processes or defects in DNA damage repair, confer growth advantages by enabling hallmark capabilities of cancer. By the principles of clonal evolution, cancer development is characterized by the acquisition of advantageous driver mutations followed by expansion of the corresponding subclonal lineage, resulting in varying degrees of intra-tumour heterogeneity. Thus, the cancer genome encodes part of the evolutionary history of the tumour. Studying tumour evolution sheds light on the diversity of evolutionary paths to invasive disease and addresses challenges in cancer clinical management.Subclonal reconstruction algorithms are commonly applied to characterize genetic intra-tumour heterogeneity from bulk DNA sequencing data. However, it remains unclear how consistently subclonal reconstruction algorithms perform on a large cohort of real-world data, and how reconstruction solutions are influenced by somatic mutation inputs. To address this gap, I evaluated twenty-two unique subclonal reconstruction pipelines on over three-hundred tumours profiled with single-region or multi-region whole-genome sequencing. I demonstrate extensive output differences across subclonal reconstruction algorithms and reveal systematic biases introduced by SNV and CNA detection tool choice. I also quantify the extent that single-region subclonal reconstruction underestimates intra-tumour heterogeneity as compared to multi-region reconstruction. Taken together, these findings illustrate the algorithmic variability of subclonal reconstruction and provide guidance for the evaluation of tumour evolution. Elucidating the tumour evolutionary history of paired primary and metastatic lesions further enable the timing of driver mutation events and the tracing of metastatic seeding. I characterized the genomic landscape and intra-tumour heterogeneity of fourteen patients with head and neck squamous cell carcinoma and reveal the similarity between mutational profiles of primary and nodal lesions. Lymph node metastases also lacked uniquely shared subclones, suggesting parallel migration from the primary tumour as the most parsimonious migration path. These findings highlight the possibility of the early acquisition of mutations required for metastatic seeding potential in the primary tumour and demonstrate the clinical implications of the study of tumour evolution.

Department dc:contributor.department

Medical Biophysics

Year dc:date.issued

2024

Author dc:creator

• Liu, Yiyang

Advisors dc:contributor.advisor

• Kislinger, Thomas
• Boutros, Paul C

• Cancer genomics
• Cancer metastasis

Handle dc:identifier.uri

https://hdl.handle.net/1807/142546

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/142546