Abstract 1698: Copy number diversity within and across tumor types

Abstract Introduction Cancers commonly accrue copy number gains and losses during their development. An improved understanding of their contribution to tumorigenesis can be gained by studying their distribution and evolution within and across tumor types. Materials and Methods We analyzed copy number profiles of 16,765 tumours from the Hartwig Medical Foundation, Pan-Cancer Analysis of Whole Genomes (PCAWG) and The Cancer Genome Atlas (TCGA) cohorts. We used a novel timing method, ComplexTiming, to time the occurrence of copy number gains, and a permutation-based approach to assess the distribution of copy number events relative to a null distribution. Results Complex copy number states in cancers that have undergone a whole-genome duplication (WGD) are commonly assumed to develop through a most parsimonious route, where the series of events leading to the complex copy number state requiring the least number of steps, is proposed to be the most likely one. Our newly developed ComplexTiming approach allows unique insights into the actual routes that led to these complex copy number states. In our large pan-cancer cohort, we found that the most parsimonious set of events does not occur in approximately 40% of cases. Additional gains more frequently occurred after WGD than before, reflecting a previously observed increase in instability. In squamous cell lung cancer, gains of 3q were frequently found before WGD. Additionally, 5q and 1q were significantly more likely to be gained before WGD in colorectal and melanoma metastases, respectively. Evaluating the distribution of copy number events, we found that the majority of copy number events are distributed across tumors consistent with a permutation model that assigns copy number events randomly. However, interestingly, in the majority of cancer types, we found copy number events that occurred more often than expected in individual tumors with low numbers of events, such as loss of chromosome 9 in bladder cancer, loss of 20p in colorectal adenocarcinomas, and gain of 1q in breast adenocarcinomas. These results suggest that the high-frequency of these specific copy number events is due to selection, while other copy number changes may occur neutrally due to innate chromosome instability. Conclusion The landscape of copy number gains in tumors is diverse. By analyzing the timing of these events as well as their distribution, we identify a subset of frequent copy number changes in different cancer types that are likely under selection. Citation Format: Toby Baker, Stefan Dentro, Paul Spellman, Maxime Tarabichi, Peter Van Loo. Copy number diversity within and across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1698.