Pb1708: characterization of global cytogenomics features in childhood acute lymphoblastic leukemia by optical genome mapping

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: Childhood acute lymphoblastic leukemia (cALL) is the most common childhood malignancy comprising multiple genetic alterations, i.e., structural and sequence mutations. In the past few years, great advances in understanding the biology of cALL by molecular and cytogenetic techniques such as next generation sequencing, karyotyping and FISH have been achieved. Optical Genome Mapping (OGM) has recently arises as a new technology capable of describing whole genome structural and copy number variations with a higher resolution than conventional cytogenetic techniques. Aims: To identify global cytogenomic alterations in diagnostic samples of cALL by OGM. Methods: Cellular samples from diagnostic bone marrow aspirates of 97 patients with cALL were processed for OGM. In brief, the ultra-high molecular weight gDNA from cALL samples was extracted, labelled and loaded into chips to run in the Saphyr platform (Bionano Genomics). Collected data was analyzed by Bionano Access 1.6 software. A binary matrix (presence/absence of each genomic alterations) was created with the chromosomal variants data, then clustering tests were performed to assess for clinical correspondence. In addition, all chromosomal variations were annotated to identify the genes involved. Furthermore, enrichment studies were performed to identify altered cellular pathways and a linkage test was carried out by the STRING interaction database. Results: We obtained a full concordance with previously diagnostic results obtained by conventional cytogenetic techniques and also found novel variants that may help in classification and could indicate common processes required for the development of ALL. CNVs losses and deletions represented almost 50% of all chromosomal alterations found. The number of alterations was diverse among patients ranging from 3 to 300 per sample. Clusters provided by K-Means algorithm based in chromosomal alterations were significantly correlated with lineage. The enrichment analysis identified recurrent involvement of known important pathways in leukemia, such as JAK-STAT. Moreover, an abundant number of immune pathways were altered, particularly those in lost regions, suggesting that the loss of immune functions probably is key for leukemia development. Network protein interaction using STRING database corroborated the involvement of the above mentioned pathways. Summary/Conclusion: The analysis of cytogenomic variations by OGM emerges as a powerful tool to improve the knowledge of the events that underlie cALL biology. Keywords: Cytogenetics, Chromosomal abnormality, Acute lymphoblastic leukemia, Childhood