Poor Prognosis Associated with Gains of CCND1 in Mantle Cell Lymphoma Treated By First Line Immuno-Chemotherapy — a Study By the Lysa Group
Authors: LE Bris Yannick , Theisen Olivier , Moreau Anne , Magrangeas Florence , Canioni Danielle , Burroni Barbara , Thieblemont Catherine , Oberic Lucie , Bouabdallah Krimo , Gyan Emmanuel , Chiron David , Pellat-deceunynck Catherine , Tessoulin Benoit , Godon Catherine , Delfau Marie-Helene , Callanan Mary , Minvielle Stephane , Bene Marie C , Hermine Olivier , LE Gouill Steven 
Published: October 2019

Abstract
Background
Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14) balanced translocation, involving on chromosome 11 the gene encoding cyclin D1, CCND1. The enhancer of IGH, on chromosome 11, induces aberrant Cyclin D1 overexpression. A few reports have shown that the CCND1 oncogene locus is a recurrently amplified region in MCL. However, the prognostic value of this copy number abnormality (CNA) is not known. The incidence and clinical impact of CCND1 CNA were investigated on diagnostic samples from patients enrolled in the first-line randomized controlled trial LyMa (S. Le Gouill et al. NEJM 2017).
Patients and methods
A series of 100 lymph node biopsies performed at diagnosis for patients enrolled in the LyMa trial (n=299) was selected. After DNA extraction, CNAs were investigated in these samples using the innovative Oncoscan® SNP-array technique adapted to analyze highly degraded DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues. Ninety-four samples were informative for CNAs. CCND1 gains were controlled by fluorescence in situ hybridization on interphase nuclei, following standard procedures using LSI IGH/CCND1 XT Dual color, dual fusion translocation probes (Abbott Molecular, Des Plaines, IL). Progression-free and overall survivals were calculated from the date of inclusion until relapse/death or last news and death or last news respectively. Cumulative incidence of relapse (CIR) was estimated from the date of inclusion until the date of relapse or last news
Results
Amplifications of a large portion of 11q, beginning at the t(11;14) breakpoint, were observed with Oncoscan® in 7 patients. All these cases with a gain of 11q13-14 (CCND1) also had a gain of the 14q32 locus (IGH) suggesting amplification of the rearranged IGH-CCND1 region of t(11;14). This was confirmed by FISH analysis which disclosed three different configurations. The first was the classical CCND1-IGH rearrangement (CCND1 on normal chromosome 11, IGH on normal chromosome 14 and two fusion signals from the t(11;14)(CCND1-IGH)). The second configuration associated CCND1-IGH fusion signals and a gain of both CCND1 and IGH signals. The third configuration was a duplication of a CCND1-IGH fusion signals (3 signals). Both in SNP and in FISH, the amplification was always identified as sub-clonal, concerning only part of the cells. In some patients, different configurations coexisted.
Compared to other patients of the series, those with amplification of IGH and CCND1 regions had a higher-risk bio-MIPI (11q13-14, p=0.015; 14q32, p=0.004). Patients with large gains at 11q13-14 (CCND1 N=7) had poorer median PFS (18 months vs not reached (NR); p=0.004), OS (35 months vs NR; p=0.01) and CIR (33 months vs not NR; p=0.004). The same was observed for patients with gains at 14q32 (IGH; N=8), with significantly different median PFS (23 months vs NR; p<0.001), OS (38 months vs NR; p=0.001) and CIR (28 months vs NR; p<0.001).
Conclusion
Gains of the IGH-CCND1 rearrangement or involved genes appear to be a potential new biomarker predictive of poor response to first line immunochemotherapy in young MCL patients.

Disclosures
Hermine: Novartis: Research Funding; Hybrigenics: Research Funding; AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Erythec: Research Funding; Celgene Corporation: Research Funding.