Cracking the pattern of tumor evolution based on single-cell copy number alterations

Copy number alterations (CNAs) are a key characteristic of tumor development and progression. The accumulation of various CNAs during tumor development plays a critical role in driving tumor evolution. Heterogeneous clones driven by distinct CNAs have different selective advantages, leading to differential patterns of tumor evolution that are essential for developing effective cancer therapies. Recent advances in single-cell sequencing technology have enabled genome-wide copy number profiling of tumor cell populations at single-cell resolution. This has made it possible to explore the evolutionary patterns of CNAs and accurately discover the mechanisms of intra-tumor heterogeneity. Here, we propose a two-step statistical approach that distinguishes neutral, linear, branching and punctuated evolutionary patterns for a tumor cell population based on single-cell copy number profiles. We assessed our approach using a variety of simulated and real single-cell genomic and transcriptomic datasets, demonstrating its high accuracy and robustness in predicting tumor evolutionary patterns. We applied our approach to single-cell DNA sequencing data from 20 breast cancer patients and observed that punctuated evolution is the dominant evolutionary pattern in breast cancer. Similar conclusions were drawn when applying the approach to single-cell RNA sequencing data obtained from 132 various cancer patients. Moreover, we found that differential immune cell infiltration is associated with specific evolutionary patterns. The source code of our study is available at https://github.com/FangWang-SYSU/PTEM.