NGS-Based Comparative Analysis of Multiple Myeloma According to 1q21Gain

초록

Introduction: Chromosome 1q gain (1q+) is one of the most common secondary cytogenetic abnormalities in multiple myeloma (MM) and is recognized as an adverse prognostic factor. Genes located on chromosome 1q (e.g., CKS1B, MCL1, ADAR1) play important roles in cell proliferation, treatment resistance, and clonal evolution. Although conventional fluorescence in situ hybridization (FISH) can detect these abnormalities, next-generation sequencing (NGS) provides a more comprehensive genomic perspective, including small variant, copy number variation (CNV), and structural variants. This study aimed to determine whether MM patients with 1q gain and concomitant IGH rearrangements exhibit distinct genomic patterns. Methods: A total of 124 patients diagnosed with multiple myeloma between January 2022 and September 2025 at Korea University Medical Center were included in this study. For cytogenetic evaluation, fluorescence in situ hybridization (FISH) analyses targeting IGH::FGFR3, IGH::MAF, IGH::CCND1, 1q21 gain/1p32 deletion, del(13q), and del(TP53) were performed on CD138+ plasma cell–enriched samples. Targeted next-generation sequencing was performed on unenriched bone marrow aspirate samples using targeted myeloma gene panels. Somatic variants were interpreted according to 2022 ClinGen/CGC/VICC guidelines, and only Tier I, II variants were analyzed. Result: Among 124 MM patients, 1q gain was observed in 61 cases (49.2%). Concomitant IGH rearrangements were present in 33 of these cases, most commonly IGH::FGFR3 (n = 15), followed by IGH::CCND1 (n = 13) and IGH::MAF (n = 5) in FISH analysis. Among patients with 1q gain, the most frequent concomitant IGH rearrangement was IGH::FGFR3, observed in 15 of 61 cases (24.6%). In contrast, IGH::CCND1 was the most common rearrangement in patients without 1q gain, occurring in 24 of 63 cases (38.1%). In the 1q gain without IGH arrangement group, oncogenic variants were identified in KRAS, RB1, NRAS, BRAF, and TP53, in that order. In the 1q gain with IGH rearrangement group, oncogenic variants were identified in KRAS, TP53, NRAS, ASXL1, and IRF4, in that order. In contrast, in the group without 1q gain, oncogenic variants were observed in NRAS, KRAS, BRAF, TET2, and TP53, in that order. Conclusion: Oncogenic variant analysis demonstrated that multiple myeloma with 1q gain exhibits a distinct genomic profile characterized by the accumulation of activating oncogenic signaling variants together with recurrent oncogenic alterations affecting tumor suppressor genes. This pattern was observed in both 1q gain subgroups with and without IGH rearrangements, whereas cases without 1q gain were predominantly associated with isolated oncogenic signaling and epigenetic modifier mutations.