Abstract
Cancer evolution is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. In this talk I will describe how single cell DNA and ATAC sequencing can contribute to our understanding of cancer evolution. I will describe Alleloscope, a method for allele-specific copy number estimation that can be applied to single- cell DNA and/or ATAC sequencing data, enabling combined analysis of allele-specific copy number and chromatin accessibility. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. These types of haplotype specific “mirrored” subclonal events have been under- reported due to lack of methods of their detection, and their role in cancer evolution is not yet clear. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling dissection of the contributions of chromosomal instability and chromatin remodeling to tumor evolution.