PS1365 NEXT‐GENERATION OPTICAL MAPPING REVEALS LARGE GENETIC HETEROGENEITY IN MULTIPLE MYELOMA

• Published in: HemaSphere 2019-06, Vol.3 (S1), p.623-624
• Main Authors: Petrackova, A., Fillerova, R., Minarik, J., Mikulkova, Z., Balcarkova, J., Krhovska, P., Pika, T., Gajdos, P., Behalek, M., Papajik, T., Kriegova, E.
• Format: Article
• Language: English
• ISSN: 2572-9241; 2572-9241
• DOI: 10.1097/01.HS9.0000563736.83709.fd

Background: Genetic heterogeneity in multiple myeloma (MM) affects not only the disease development but also therapeutic response and prognosis. Nowadays, karyotype and FISH are standard diagnostic tools for the detection of genetic aberrations in MM. However, comprehensive analysis of genome architecture, particularly structural variations (SVs), still remain a challenge. Aims: To study the genomic architecture of MM cells using a novel nanochannel technology based on optical mapping of high‐molecular weight DNA in order to refine genomic variability in human MM. Methods: We analysed five samples of bone marrow aspirates from patients with newly diagnosed MM. High‐molecular weight DNA was isolated from sorted MM cells, labelled by DLS chemistry and visualised by Saphyr optical system (BioNano Genomics). Created single molecules were de novo assembled into physical maps spanning whole genome based on known labelled specific motifs. After filtering of structural variants against the database of healthy controls, only rare de novo variants were analysed. Karyotype, FISH, and arrayCGH results were available for the enrolled patients and were compared to the results of optical mapping. Results: For all MM samples, the optical genome maps (480 Gbp) were assembled with an average effective coverage of 124X and aligned to a human reference genome (GRCh38). In our cohort, numerous copy number variations and large somatic SVs, including deletions, insertions, inversions, duplications and translocations, were identified (Table 1) with majority of SVs being deletions (∼60%). All genetic variants detected by arrayCGH were also confirmed by mapping. Additional SVs with novel intra‐ and inter‐chromosomal translocations and copy number variants were found in all patients, not detected by FISH/arrayCGH. Regarding novel translocations, majority were intra‐chromosomal (64%) within chromosomes 3, 4, 6, 14, 16, 17, and 18. Additional translocations (36%), detected only by mapping, involved unusual chromosomes in MM: t(2;8), t(3;6), t(3;12), t(6;8), t(6;17), t(8;9), and t(8;22). All samples carried novel SVs on chromosome 17, including two intra‐ (P1) and one inter‐chromosomal translocations (P2), insertions in four (P2‐P5) and deletions in two (P4‐P5) patients. Although no IGH locus rearrangements were detected by standard methods, monosomy on chromosome 14 within IGH locus was observed in four samples (P2‐P5) by mapping. The analyses of associations of SVs and affected genes