Abstract 3769: Detection of allele specific loss of heterozygosity in 70,000 patients with ctDNA

Abstract

Abstract Background: Loss of Heterozygosity (LoH) is a common feature of tumor biology. LoH frequently arises from defects in Homologous Recombination Repair (HRR) and results in uni-parental deletions that manifest as (LoH). In the absence of a driving force, the likelihood of allelic loss is equal, so in a population, the rate of retention and loss of a given allele is equal, but allele specific loss (or retention) is known to occur. Methods: Using a novel analysis method incorporating observed allele frequency and copy number variation, we investigated the Guardant Health database of variants detected from 70,000+ samples from whole blood samples from patients with advanced solid tumors that were tested using a 73-gene cell-free DNA next-generation sequencing panel (Guardant360, Guardant Health, Redwood City, CA) to identify allele specific loss. Results: Analysis of the Guardant Health database revealed that LoH frequently manifests as allele imbalance with the observed mutation allele frequency (MAF) of the retained allele exceeding an observed allele frequency of 50% and the lost allele having observed mutation allele frequencies below 50% in an individual sample. This imbalance occurs because allele frequency is a relative measurement and loss of one allele causes the relative abundance of the remaining allele to increase in a proportional amount. Population analysis reveals that the majority of of alleles are lost without preference, but certain alleles may be more prone to retention or loss. Conclusions: The detection of allele specific loss from ctDNA provides insight into the underlying tumor biology and the selective pressures shaping tumor evolution over the course of treatment. Note: This abstract was not presented at the meeting. Citation Format: Jing Zhao, Stephen R. Fairclough, Darya Chudova, Richard Lanman, AmirAli Talasaz, Aaron Hardin. Detection of allele specific loss of heterozygosity in 70,000 patients with ctDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3769.