TY - JOUR
T1 - High-resolution structural variant profiling of myelodysplastic syndromes by optical genome mapping uncovers cryptic aberrations of prognostic and therapeutic significance
AU - Yang, Hui
AU - Garcia-Manero, Guillermo
AU - Sasaki, Koji
AU - Montalban-Bravo, Guillermo
AU - Tang, Zhenya
AU - Wei, Yue
AU - Kadia, Tapan
AU - Chien, Kelly
AU - Rush, Diana
AU - Nguyen, Ha
AU - Kalia, Awdesh
AU - Nimmakayalu, Manjunath
AU - Bueso-Ramos, Carlos
AU - Kantarjian, Hagop
AU - Medeiros, L. Jeffrey
AU - Luthra, Rajyalakshmi
AU - Kanagal-Shamanna, Rashmi
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/9
Y1 - 2022/9
N2 - Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique for high-resolution genome-wide SV profiling (SVP). We explored the clinical value of SVP by OGM in 101 consecutive, newly diagnosed MDS patients from a single-center, who underwent standard-of-care cytogenetic and targeted NGS studies. OGM detected 383 clinically significant, recurrent and novel SVs. Of these, 224 (51%) SVs, seen across 34% of patients, were cryptic by CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). SVP decreased the proportion of normal karyotype by 16%, identified complex genomes (17%), chromothripsis (6%) and generated informative results in both patients with insufficient metaphases. Precise gene/exon-level mapping allowed assessment of clinically relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. SV data was complementary to NGS. When applied in retrospect, OGM results changed the comprehensive cytogenetic scoring system (CCSS) and R-IPSS risk-groups in 21% and 17% patients respectively with an improved prediction of prognosis. By multivariate analysis, CCSS by OGM only (not CBA), TP53 mutation and BM blasts independently predicted survival. This is the first and largest study reporting the value of combined SVP and NGS for MDS prognostication.
AB - Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique for high-resolution genome-wide SV profiling (SVP). We explored the clinical value of SVP by OGM in 101 consecutive, newly diagnosed MDS patients from a single-center, who underwent standard-of-care cytogenetic and targeted NGS studies. OGM detected 383 clinically significant, recurrent and novel SVs. Of these, 224 (51%) SVs, seen across 34% of patients, were cryptic by CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). SVP decreased the proportion of normal karyotype by 16%, identified complex genomes (17%), chromothripsis (6%) and generated informative results in both patients with insufficient metaphases. Precise gene/exon-level mapping allowed assessment of clinically relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. SV data was complementary to NGS. When applied in retrospect, OGM results changed the comprehensive cytogenetic scoring system (CCSS) and R-IPSS risk-groups in 21% and 17% patients respectively with an improved prediction of prognosis. By multivariate analysis, CCSS by OGM only (not CBA), TP53 mutation and BM blasts independently predicted survival. This is the first and largest study reporting the value of combined SVP and NGS for MDS prognostication.
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U2 - 10.1038/s41375-022-01652-8
DO - 10.1038/s41375-022-01652-8
M3 - Article
C2 - 35915143
AN - SCOPUS:85135271767
SN - 0887-6924
VL - 36
SP - 2306
EP - 2316
JO - Leukemia
JF - Leukemia
IS - 9
ER -