Optical Genome Mapping Reveals and Characterizes Recurrent Aberrations and New Fusion Genes in Adult ALL

Abstract

(1) Background: In acute lymphoblastic leukemia (ALL) the genetic characterization remains challenging. Due to the genetic heterogeneity of mutations in adult patients, only a small proportion of aberrations can be analyzed with standard routine diagnostics. Optical genome mapping (OGM) has recently opened up new possibilities for the characterization of structural variants on a genome-wide level, thus enabling simultaneous analysis for a broad spectrum of genetic aberrations. (2) Methods: 11 adult ALL patients were examined using OGM. (3) Results: Genetic results obtained by karyotyping and FISH were confirmed by OGM for all patients. Karyotype was redefined, and additional genetic information was obtained in 82% (9/11) of samples by OGM, previously not diagnosed by standard of care. Besides gross-structural chromosome rearrangements, e.g., ring chromosome 9 and putative isodicentric chromosome 8q, deletions in CDKN2A/2B were detected in 7/11 patients, defining an approx. 20 kb minimum region of overlap, including an alternative exon 1 of the CDKN2A gene. The results further confirm recurrent ALL aberrations (e.g., PAX5, ETV6, VPREB1, IKZF1). (4) Conclusions: Genome-wide OGM analysis enables a broad genetic characterization in adult ALL patients in one single workup compared to standard clinical testing, facilitating a detailed genetic diagnosis, risk-stratification, and target-directed treatment strategies.

Optical Genome Mapping as a New Tool to Overcome Conventional Cytogenetics Limitations in Patients with Bone Marrow Failure

“…As mentioned before, OGM's utility has also been explored by many other groups in different conditions and has demonstrated excellent results and concordance with traditional cytogenetic analysis [2,4,5,7,9,[21][22][23]. For example, in a clinical validation study in which 92 sample runs were included (belonging to 69 samples, 59 hematological neoplasms and 10 healthy controls), OGM showed a sensitivity of 98.7%, specificity of 100% and an accuracy of 99.2% in comparison to standard techniques (karyotype analysis, FISH, and chromosomal microarray), with a 100% first-pass rate regarding the quality control metrics [2].…”

“…OGM is being increasingly implemented in cytogenetics laboratories and its use has been explored in diverse settings, including prenatal or postnatal constitutional studies, solid tumors, and diverse hematologic malignancies [3][4][5][6][7][8][9][10]. However, to our knowledge, there are no reports about its applicability in BMFSs to date.…”

Application of Optical Genome Mapping to the Risk Stratification and Treatment Optimization of Hematologic Diseases

“…No change Intensified Downgraded AML (25) 18 (72%) 7(28%) 0 ALL (17) 13 (76.47%) 4 (23.52%) 0 CLL (4) 3 (75%) 1 (25%) 0 MPN (15) 15 (100%) 0 0 MDS (5) 4 (80%) 1 (20%) 0 MPN/MDS (4) 3 (75%) 1 (25%) 0 MPAL (5) 5 (100%) 0 0 Multiple myeloma (8) 8 (100%) 0 0 Lymphoma (11) 11 (100%) 0 0 Total (94) 80 14 0…”

“…Concordance to standard clinical testing methods was published for multiple hematological malignancies [11,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Levy and colleagues published a deep dive multisite study of acute myelogenous leukemia (AML) where they revealed that OGM was 100% concordant with karyotyping and FISH and detected additional clinically relevant abnormalities missed by standard tests in 13% of cases [15].…”

Novel NUP98::ASH1L Gene Fusion in Acute Myeloid Leukemia Detected by Optical Genome Mapping

“…At our tertiary care center, OGM has been implemented in parallel to routine clinical cytogenetic testing to evaluate its feasibility in acute leukemias, as described previously [23,28,30,31]. Written and informed consent was provided for patient participation in this study and for publication.…”