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

Abstract

Optical genome mapping (OGM) recently has demonstrated the potential to improve genetic diagnostics in acute myeloid leukemia (AML). In this study, OGM was utilized as a tool for the detection of genome-wide structural variants and disease monitoring. A previously unrecognized NUP98::ASH1L fusion was detected in an adult patient with secondary AML. OGM identified the fusion of NUP98 to Absent, Small, or Homeotic-Like Histone Lysine Methyltransferase (ASH1L) as result of a complex structural rearrangement between chromosomes 1 and 11. A pipeline for the measurement of rare structural variants (Rare Variant Pipeline, Bionano Genomics, San Diego, USA) was used for detection. As NUP98 and other fusions are relevant for disease classification, this demonstrates the necessity for methods such as OGM for cytogenetic diagnostics in AML. Furthermore, other structural variants showed discordant variant allele frequencies at different time points over the course of the disease and treatment pressure, indicating clonal evolution. These results support OGM to be a valuable tool for primary diagnostics in AML as well as longitudinal testing for disease monitoring and deepening our understanding of genetically heterogenous diseases.

Detection of Genomic Structural Variations Associated with Drug Sensitivity and Resistance in Acute Leukemia

“…In sum, these data strengthen the suggestions of several previous studies that OGM can be superior to traditional cytogenetics in uncovering both known and novel SVs [26][27][28][29][30][31][32][33][34] and further suggest that OGM is potentially capable of tracking patient disease progression and clonal variation [20,33].…”

“…Interestingly, this translocation was not predicted to result in gene fusion; however, a t(2;11) translocation resulting in a NUP98::ASH1L gene fusion has been previously reported in AML and was in fact detected at the time using OGM [20]. The study by Tembrink et al that describes this NUP98::ASH1L gene fusion further describes how sub-clonal SVs develop during AML disease progression [20]. Unfortunately, we do not have any remaining pre-treatment samples from this patient.…”

“…Nevertheless, our As an example of a novel finding with potential disease relevance, sample −009NR was obtained from a patient after relapse (NR, "non-responder"), and, although Chr.7 monosomy was known to exist upon the initial presentation, a translocation (t(2;11)) had not been reported in the original sample prior to relapse using traditional cytogenetics (Figure 2B). Interestingly, this translocation was not predicted to result in gene fusion; however, a t(2;11) translocation resulting in a NUP98::ASH1L gene fusion has been previously reported in AML and was in fact detected at the time using OGM [20]. The study by Tembrink et al that describes this NUP98::ASH1L gene fusion further describes how sub-clonal SVs develop during AML disease progression [20].…”

“…This system has been used and validated extensively by multiple groups, spanning diverse applications such as genome assembly [5], facioscapulohumeral muscular dystrophy (FSHD) [6,7], Duchenne muscular dystrophy (DMD) [8], and SV detection in chimpanzee (Pan troglodytes) subpopulations [9,10]. Furthermore, relevant to this study, the platform has also been utilized to uncover novel variants in diverse types of cancer [11], including prostate cancer [12], liposarcoma [13], and multiple leukemia indications [4,[14][15][16][17][18][19][20][21][22]. This technique can detect SVs at a ~5% allele fraction, thus allowing for the inference of clonal populations with distinct SVs [20].…”

“…Furthermore, relevant to this study, the platform has also been utilized to uncover novel variants in diverse types of cancer [11], including prostate cancer [12], liposarcoma [13], and multiple leukemia indications [4,[14][15][16][17][18][19][20][21][22]. This technique can detect SVs at a ~5% allele fraction, thus allowing for the inference of clonal populations with distinct SVs [20].…”