Abstract 406: Characterization of whole genome duplication in a genomic cohort of over 14000 cell free DNA samples
Authors: Gross Andrew , Wang Hao , Tolkunov Denis , Jenkins Colby , Wienke Sara , Barbacioru Catalin , Chuang Han-Yu 
Published: March 2024

Background: Wide-scale rates of whole genome duplication (WGD) have previously been demonstrated in studies performed in tissue among genomically characterized tumors. Such studies report varied rates of WGD depending on tumor type and stage. Hallmarks of WGD include widespread loss-of-heterozygosity as well as associations with tumor proliferation and specific oncogenic driver events such as loss of function TP53 mutations. It has been proposed that presence of WGD could be a poor prognostic biomarker, leading to interest in profiling this genomic landmark in large retrospective cohorts to inform future clinical studies.

Methods: Samples that were run through the GuardantOMNI high content genomic profiling assay using cfDNA extracted from blood were analyzed. Only samples originating from individuals with primary breast, colorectal, or prostate cancer were considered due to limited sample size in other indications. We deployed a likelihood-based copy-number variant caller, which jointly selects tumor purity and ploidy while fitting normalized coverage and germline variant allele frequencies across genome-wide data. Only samples where we predicted to have greater than 10% tumor fraction from copy number variant (CNV) profiles were considered for statistical analysis. The presence of whole genome duplication was assessed by counting the median major chromosomal copy number. Presence of SNV/InDels were annotated, assessed for pathogenicity, and filtered to those with a pathogenic allele frequency greater than 10%.

Results: A total of 14,076 samples were analyzed, with 5362 passing the 10% observed tumor fraction cutoff. WGD was annotated in 2195 (41%) samples with varying rates across sub-cohorts (31%, 36%, and 54% of breast, colorectal, and prostate cancer, respectively). Mutation in TP53 was associated with a large increase in rate of WGD (odds ratio 6.9, 95% CI 6.1-7.8) which is consistent but higher in magnitude to similar studies in tissue samples. Amplification of CCNE1 and homozygous deletion of genes including WRN and RB1 were also associated with WGD, independent of TP53 mutation status and overall rates of aneuploidy.

Conclusion: WGD was detected in 41% of samples with greater than 10% tumor fraction in cell-free DNA across three cancer types. While this represents a substantial percentage of advanced cancers, more research needs to be done regarding the impact of these events on clinical outcomes and treatment response. Additionally, co-occurrence of these events with other advanced cancer biomarkers such as microsatellite instability or homologous recombination deficiency was not reported. Given the high rates of these events, future retrospective studies are warranted to correlate presence of WGD with patient outcomes and response.

Citation Format: Andrew Gross, Hao Wang, Denis Tolkunov, Colby Jenkins, Sara Wienke, Catalin Barbacioru, Han-Yu Chuang. Characterization of whole genome duplication in a genomic cohort of over 14000 cell free DNA samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 406.