Author ORCID Identifier
https://orcid.org/0000-0001-9179-7577
Date of Graduation
12-2024
Document Type
Dissertation (PhD)
Program Affiliation
Genetics and Epigenetics
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Nicholas Navin
Committee Member
Jeffrey Chang
Committee Member
Hui Chen
Committee Member
Ralf Krahe
Committee Member
Luay Nakhleh
Committee Member
Peter Van Loo
Abstract
Aneuploidy is a hallmark of human cancers, with many copy number aberrations (CNAs) being associated with disease progression. Previous studies have revealed extensive inter-patient heterogeneity (IPH) in copy number profiles. However, the extent of intratumoral heterogeneity (ITH) and its evolutionary dynamics remain poorly understood.
To address these gaps, we developed Acoustic Cell Tagmentation (ACT), an advanced single-cell single-molecule DNA sequencing (scDNA-seq) technology, to resolve the copy number substructure of human tumors and investigate the evolution of aneuploidy. Applying ACT to eight triple-negative breast cancer (TNBC) patients to profile 9,765 aneuploid tumor cells, we discovered that following initial punctuated copy number evolution (PCNE), a short period of transient genome instability led to the generation of many tumor subclones (7-22) that grouped into 3-5 major superclones.
We then extended the application of ACT to a pan-cancer study involving 94 tumors across seven major cancer types: bladder, breast, colon, glioblastoma, kidney, lung, and ovarian. Single-cell copy number profiling was used to analyze 62,646 aneuploid cells, and bulk exome sequencing was performed on 84 out of 94 patients. We found that increased copy number diversity was associated with elevated CNA burden, TP53 mutations, and whole-genome doubling (WGD). Additionally, we identified instances of subclonal WGD, suggesting that tumor cells lose more chromosomes after WGD, resulting in distinct copy number profiles. Our findings indicate that most solid tumors originate from a single ancestral cell with many shared truncal CNAs or mutations, and that PCNE is prevalent across different cancer types. Furthermore, we observed a correlation between high copy number diversity and spatial heterogeneity. This work significantly enhances our understanding of intratumoral copy number heterogeneity across human cancers.
Keywords
pan-cancer, punctuated evolution, single cell genomics, tumor heterogeneity, cancer genomics, tumor evolution
Included in
Bioinformatics Commons, Biotechnology Commons, Cancer Biology Commons, Computational Biology Commons, Genomics Commons