A comprehensive approach to evaluate genetic abnormalities in multiple myeloma using optical genome mapping
Ying Zou, Melanie Klausner, Jen Ghabrial, Victoria Stinnett, Patty Long, Laura Morsberger, Jaclyn B. Murry, Katie Beierl, Christopher D. Gocke, Rena R. Xian, Kevin H. Toomer, Jing Christine Ye, Robert Z. Orlowski, Carol Ann Huff, Syed Abbas Ali, Philip Imus, Christian B. Gocke, Guilin Tang
Abstract
Multiple myeloma (MM) is a plasma cell neoplasm (PCN) [ 1 ]. Sensitive and accurate identification of genetic abnormalities is critical for patient risk stratification and therapeutic decision-making as well as understanding pathogenesis. Recurring genetic abnormalities include structural variants (SVs), such as rearrangements involving IGH and MYC genes; copy number variants (CNVs), such as 1q+, del(17p), del(13q); hyperdiploidy/hypodiploidy; and various gene mutations, such as mutations in the RAS pathway, BRAF, FAM46C, DIS3 , and TP53 [ 2 ]. Trisomies/hyperdiploidy and IGH rearrangements/fusions are considered primary abnormalities present at disease initiation while 1q+, del(17p)/ TP53 mutations and MYC rearrangements/fusions are considered secondary abnormalities that develop during disease progression [ 3 ]. High-risk genetic abnormalities including del(17p), t (4;14)/ IGH::FGFR3 / NSD2 , and t (14;16)/ IGH::MAF have been used along with serum markers for MM risk stratification in the Revised International Stage System [ 4 ]. Other genetic abnormalities including t (14;20)/ IGH::MAFB , and MYC rearrangements/fusions are considered potential high-risk biomarkers in MM [ 2 ]. Recently whole-genome sequencing (WGS) studies have revealed novel candidate driver genes and catastrophic complex rearrangements (chromoanagenesis) associated with poor clinical outcomes [ 5 ]. Furthermore, the presence of some genetic abnormalities can clearly impact response to specific therapies, as exemplified by t (11;14)/ IGH::CCND1 and response to BCL2 inhibition [ 2 , 3 , 6 ]. Therefore, detection of genome-wide genetic abnormalities is essential.