Abstract 5263: Whole-genome sequencing as an alternative to analyze copy number abnormalities in acute myeloid leukemia and myelodysplastic syndrome
Authors: Lyu Xiaodong , Li Tao , Zhu Dandan , Zhang Mengna , Cheng Yuexin , Chen Yan , Li Zhenling , Li Shiyong , Wu Wei , Geng Shuaipeng , Li Jingshuai , He Xiangxiang , Li Yangwei , Chang Yinyin , Zhu Zunmin , Mao Mao , Song Yongping 
Published: June 2022

Abstract
Genomic alternations especially copy number aberrations (CNAs) are particularly imperative for diagnostic classification and risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Although conventional cytogenetic analysis (CCA) has been mandatory in clinical routine to detect recurrent genomic abnormalities in AML/MDS, it presents a few obvious shortcomings, such as time-consuming in vitro cell-culturing procedure, low resolution (no smaller than 10 Mbp), and subjective bias introduced from the visual interpretation by cytogeneticists. With the technological advances of next generation sequencing (NGS), the current CCA test and the molecular tests are likely to be challenged by whole-genome sequencing (WGS), which is a more unbiased method to detect all types of genomic aberrations not only those well-characterized clinically actionable mutations but also cryptic alternations yet to be defined and annotated. In this study a shallow whole-genome sequencing (sWGS) based assay, LeukoPrint, was utilized to depict genomic CNA profiles from the bone marrow cells of 107 newly diagnosed patients with AML (n=63, 58.9%) or MDS (n=44, 41.1%). Bone marrow was collected and mononuclear cells were separated to harvest genomic DNA which was sequenced without capture at approximately 1x coverage depth. Genome-wide CNAs was analyzed for each sample using an automated pipeline. European Leukemia Net (ELN) or Revised International Prognostic Scoring System (IPSS-R)-defining CNAs were selected and used to assign patients to a genetic risk group through the same classification systems that are used for CCA. It demonstrated 98.1% concordance of CNA profiles at individual patient level with cytogenetics and/or FISH. It is advantageous in detecting CNAs of short segments (1 Mb) and from samples with low leukemic cell content, more accurate for describing complex karyotypes and less confounded by subjective bias. LeukoPrint improved the overall diagnostic yield by redefining the risk categories for 16 patients (15%) by presenting new information. Nearly identical CNA profiles from the paired plasma and bone marrow suggest that peripheral blood may serve as a substitute to spare bone marrow aspiration. In summary, LeukoPrint provided an automated, convenient and cost-effective approach to describe genomic CNA profiles in AML/MDS. It brought greater diagnostic yield and risk stratification information by incorporating into the routine cytogenetics based on the standard ELN/IPSS-R guidelines.
Citation Format: Xiaodong Lyu, Tao Li, Dandan Zhu, Mengna Zhang, Yuexin Cheng, Yan Chen, Zhenling Li, Shiyong Li, Wei Wu, Shuaipeng Geng, Jingshuai Li, Xiangxiang He, Yangwei Li, Yinyin Chang, Zunmin Zhu, Mao Mao, Yongping Song. Whole-genome sequencing as an alternative to analyze copy number abnormalities in acute myeloid leukemia and myelodysplastic syndrome [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 5263.