Abstract 1152: The landscape of copy number variations following WGD in 5,980 colorectal cancers

Abstract Introduction: Whole-genome doubling (WGD), marked by the duplication of all chromosomes, is widespread in cancer with significant prognostic implications. Traditionally, WGD tumors are assumed to exist in the tetraploid state. However, the evolutionary selection pressures following WGD and their effects on aneuploidy and patient outcomes remain poorly characterized. Methods: We analyzed 5, 980 tumor samples from 5, 807 patients with colorectal cancer treated at Memorial Sloan Kettering between 2014 and 2024. Tumors were sequenced using the targeted MSK-IMPACT clinical sequencing assay. Arm-level copy number variation (CNV) was inferred using FACETS, an allele-specific copy number algorithm. Copy number states were defined by the total copy number to minor copy number ratio, defining the diploid state as 2:1, triploid state as 3:1, and tetraploid state as 4:2. Tumors were classified as WGD-positive (WGD+) if >50% of their autosomal genome had a major copy number ≥2; otherwise, they were classified as WGD-negative (WGD−). The fraction of genome altered (FGA) for WGD+ tumors was calculated as the proportion of the genome deviating from the triploid state. Chromosome arms were assigned selection scores based on the potency and distribution of oncogenes and tumor suppressor genes. Results: Both WGD- and WGD+ tumors exhibited selective arm-level gains and losses, but these pressures were weaker in WGD+ tumors (Pearson r=0.46 vs. 0.32). WGD+ tumors exhibited an average ploidy of 2.7, with the triploid state as the predominant allelic configuration, comprising 35.8% of the genome on average compared to the tetraploid state (9.7%). The triploid state more closely mirrored the arm-level selection patterns of the diploid state in WGD- tumors than the tetraploid state (Spearman r=0.88 vs. 0.27), a relationship further confirmed by clustering analysis of arm-level CNVs in microsatellite stable (MSS) colorectal cancers (n=4899). Using FGA as a measure of overall aneuploidy, we identified that MSS WGD+ colorectal cancer patients (n=1975) in the lowest FGA quartile had improved overall survival (OS) compared to those in the highest quartile (median OS: 28.1 vs. 24.8 months, p=0.003). Prior chemotherapy exposure was associated with a significant increase in WGD prevalence in MSS colorectal cancer patients with matched samples (n=90, 49% vs. 68%, p=0.015). Conclusions: Our study identifies the triploid state as the predominant and presumably biologically optimal allelic configuration of WGD+ tumors. The FGA metric highlights the clinical relevance of the triploid state in patient stratification, while the observed link between chemotherapy and increased WGD prevalence suggests potential therapeutic implications for colorectal cancer. These findings advance our understanding of WGD-driven aneuploidy and its role in cancer evolution and treatment strategies. Citation Format: Jierui Xu, Henry Walch, Paolo Manca, Maria Perry, Christopher Fong, Justin Jee, Karl Pichotta, Efsevia Vakiani, Neil H. Segal, Adam Price, Allison L. Richards, Chai Bandlamudi, Mark Donoghue, Andrea Cercek, Rona Yaeger, Nikolaus Schultz, Walid K. Chatila. The landscape of copy number variations following WGD in 5, 980 colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1152.