Background: The IGH::CCND1 rearrangement, resulting from a translocation between chromosomes 11q13 and 14q32, is one of the most common genetic abnormalities in multiple myeloma (MM) and defines a distinct subtype with B-cell-like features, including CD20 expression. Fluorescence in situ hybridization (FISH) is a critical diagnostic tool in routine practice for detecting this and other genetic alterations in MM. Typical positive FISH patterns of IGH::CCND1 rearrangement using double fusion (F) probe sets (Red (R): CCND1 and Green (G):IGH) include 2F1R1G indicating a balanced t(11;14) abnormality and 2F2R1G indicating balanced t(11;14) and coexisting trisomy 11 (signals for fusion and 11 centromere probe, CEP11 in the same FISH panel with similar percentages) . However, atypical IGH::CCND1 FISH patterns (any deviation from the typical configurations) are often observed in MM cases. The clinical significance of these variations remains unclear.

Methods: We analyzed 226 MM cases positive for IGH::CCND1 rearrangement by FISH diagnosed between January 2010 and May 2025. Cases were categorized into two groups: typical fusion patterns (Group I, n=119; 52.65%) and atypical fusion patterns (Group II, n=107; 47.35%). Group characteristics were compared using X2test.

Results: Group I included 82 males and 38 females, ages from 39 to 85 years with median age of 68.9; Group II included 68 males and 39 females, ages from 37 to 88 years with median age of 65.7. Further analysis showed that IGH::CCND1 rearrangement was the sole FISH abnormality in 51.26% cases in Group I, versus 34.58% of cases in Group II (p=0.016), indicating that group II has higher percentage of cases with additional chromosomal aberration(s). The most common concurrent abnormality was monosomy 13 (concurrent loss of 13q14 and 13q34) in both groups, but the percentage was significantly lower in group I than in group II (22.69% versus 37.38%, p=0.023). Notably, coexisting TP53 deletion was observed more frequently in group II than in group I (28.04% versus 5.88%, p=0.00016). The prevalence of coexisting 1q gain (18.69% versus 8.40%, p=0.038), trisomy 9 (28.04% versus 6.72%, p= 4.14E-05) and trisomy 11 (24.42% versus 7.56%, p=0.013) was significantly higher in group II than in group I. There was no significant difference between the groups in terms of CD20 expression (33.72% vs. 23.16%, p=0.16).

Conclusion: MM with atypical IGH::CCND1 fusion patterns is associated with a higher number of concurrent cytogenetic alterations compared to typical patterns of IGH::CCND1 fusion. The higher prevalence of TP53 deletion associated with atypical IGH::CCND1 fusion patterns may explain these increased cytogenetic changes because of the insufficient DNA repairing function of TP53 leading to chromosome instability. Higher frequency of 1q gain (an unfavorable prognostic factor) in group II may also have important clinical implications. These findings suggest that IGH::CCND1 FISH pattern variations may have diagnostic and prognostic relevance in MM and warrant further investigation.

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2025
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