Optical genome mapping reveals diverse mechanisms of cyclin activation in mantle cell lymphomas lacking IGH::CCND1.

The t(11;14)(q13; q32)/IGH::CCND1 is a genetic hallmark of mantle cell lymphoma (MCL), reported to be present in about 95% of cases. In this study, we performed optical genome mapping (OGM) on 91 patients with MCL, in conjunction with next-generation sequencing (NGS), conventional chromosomal analysis and fluorescence in situ hybridization (FISH). The t(11;14)/IGH::CCND1 was detected in 82 cases, whereas 9 (10%) cases lacked this abnormality. OGM and NGS identified alternative CCND1 abnormalities in 7 cases: IGK::CCND1 (n = 3), IGL::CCND1 (n = 1), an insertion adjacent to the 5' region of CCND1 (n = 1); a deletion at the 5' region of CCND1 (n = 1), and a mutation in the 3' untranslated region of CCND1 (n = 1). OGM detected CCND2 rearrangement with IGK or IGL in the other 2 cases. All 7 cases exhibiting CCND1 aberrations expressed cyclin D1, although some lacked SOX11 or CD5 expression. The two cases with CCND2 rearrangement were SOX11-positive. Six cases showed highly complex genome detected by OGM and the affected patients were refractory to chemotherapy and/or had poorer survival. In conclusion, approximately 10% of MCL cases lack the classic t(11;14)/IGH::CCND1. OGM is valuable in identifying variant CCND1 and CCND2 rearrangements, and the presence of high genome complexity may correlate with treatment resistance and poor outcomes.