Impact of shallow whole genome sequencing on diagnostic yield and prognostic precision in myelodysplastic syndromes.

Abstract

6567 Background: Accurate cytogenetic characterization is critical for risk stratification in myelodysplastic syndromes (MDS). Conventional karyotyping and fluorescence in situ hybridization (FISH) are limited in resolution, target specific loci, and cannot detect copy-neutral loss of heterozygosity (CN-LOH). LeukoPrint, a CE-IVD-marked shallow whole-genome sequencing (sWGS, 1×coverage) test, enables genome-wide detection of copy number alterations (CNAs) and CN-LOH. Previously validated in acute myeloid leukemia and multiple myeloma, it improved CNA detection and prognostic accuracy. This study evaluated its ability to enhance diagnostic yield and refine prognostic precision in a large MDS cohort. Methods: Bone marrow samples from 461 MDS patients were profiled for genome-wide CNA/CN-LOH using LeukoPrint. Results were compared with conventional karyotyping and FISH to assess detection yield and concordance. The impact of additional LeukoPrint findings on Revised International Prognostic Scoring System (IPSS-R) cytogenetic risk stratification and MDS subclassification was evaluated. Results: LeukoPrint detected cytogenetic abnormalities in 63.3% of patients, comprising CNAs in 50.3%, CN-LOH in 23.9%, with 10.8% harboring both. Recurrent CNAs included del(5q) (10.0%), del(20q) (10.0%), +8 (8.9%), and del(7q) (7.8%), among others. CN-LOH frequently affected regions that overlapped common CNA loci, such as 5q (3.7%), 7q (3.7%), and 17p (0.7%). Compared with conventional cytogenetics, LeukoPrint showed 94.4% concordance (κ=0.854) with FISH for five key loci (−5/del(5q), −7/del(7q), +8, del(20q), −Y) and a higher detection rate than karyotyping (65.7% vs 39.2%). For the 11 IPSS-R defined cytogenetic abnormalities (del(3q), del(5q), del(7q), del(11q), del(12p), del(17p), del(20q), +8, +19, -7, and -Y), it identified all karyotype-detected lesions and increased detection yield by 49.4%. These newly identified abnormalities led to IPSS-R cytogenetic risk reclassification in 32.4% (33/102) of comparable cases, predominantly upgrading patients to higher-risk categories. Specifically, 26 patients were reassigned from Good to Intermediate (n = 17), Poor (n = 2), or Very Poor (n = 7); 5 from Intermediate to Poor (n = 4) or Very Poor (n = 1); and 1 from Poor to Very Poor. Furthermore, by detecting additional aberrations such as del(17p) or 17p CN-LOH, LeukoPrint enabled more accurate molecular classification, including the reclassification of one case from MDS-IB1 to MDS-biTP53. Conclusions: sWGS-based LeukoPrint substantially enhances cytogenetic detection in MDS, outperforming conventional karyotyping and FISH. By identifying additional clinically relevant cytogenetic abnormalities, it improves prognostic risk stratification and refines disease classification, supporting its integration into routine MDS cytogenetic assessment.