A gene signature that distinguishes conventional and leukemic nonnodal mantle cell lymphoma helps predict outcome

Abstract

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy, but some patients have a very indolent evolution. This heterogeneous course is related, in part, to the different biological characteristics of conventional MCL (cMCL) and the distinct subgroup of leukemic nonnodal MCL (nnMCL). Robust criteria to distinguish these MCL subtypes and additional biological parameters that influence their evolution are not well defined. We describe a novel molecular assay that reliably distinguishes cMCL and nnMCL using blood samples. We trained a 16-gene assay (L-MCL16 assay) on the NanoString platform using 19 purified leukemic samples. The locked assay was applied to an independent cohort of 70 MCL patients with leukemic presentation. The assay assigned 37% of cases to nnMCL and 56% to cMCL. nnMCL and cMCL differed in nodal presentation, lactate dehydrogenase, immunoglobulin heavy chain gene mutational status, management options, genomic complexity, and / deletions, but the proportion with 17p/ aberrations was similar in both subgroups. Sequential samples showed that assay prediction was stable over time. nnMCL had a better overall survival (OS) than cMCL (3-year OS 92% vs 69%; = .006) from the time of diagnosis and longer time to first treatment. Genomic complexity and/ aberrations predicted for shorter OS in the entire series and cMCL, whereas only genomic complexity was associated with shorter time to first treatment and OS in nnMCL. In conclusion, the newly developed assay robustly recognizes the 2 molecular subtypes of MCL in leukemic samples. Its combination with genetic alterations improves the prognostic evaluation and may provide useful biological information for management decisions.

Increased tumour angiogenesis in SOX11‐positive mantle cell lymphoma

“…Our investigation included both subsets of MCL that had representative clinical and biological features of conventional and leukaemic non-nodal subtypes. 8 We observed that an increased microvascular development was associated with significantly shorter OS in the whole cohort, and a similar tendency was also seen in the two subsets of SOX11-positive and -negative tumours. These findings suggest that the angiogenic switch observed in SOX11-positive MCL may contribute to their more aggressive behaviour.…”

“…However, SOX11 expression was not evaluated in these two studies. Our investigation included both subsets of MCL that had representative clinical and biological features of conventional and leukaemic non‐nodal subtypes . We observed that an increased microvascular development was associated with significantly shorter OS in the whole cohort, and a similar tendency was also seen in the two subsets of SOX11‐positive and ‐negative tumours.…”

“…Similarly to conventional MCL, these tumours carry the t(11;14)(q13;q32) and overexpress cyclin D1, but lack expression of sex determining region‐Y‐box11 (SOX11), a transcription factor highly specific of conventional MCL . Although leukaemic non‐nodal MCL are initially indolent, they may evolve towards an aggressive disease, usually associated with 17p/ TP53 or other complex genomic alterations …”

“…[5][6][7] Although leukaemic non-nodal MCL are initially indolent, they may evolve towards an aggressive disease, usually associated with 17p/TP53 or other complex genomic alterations. 4,8 SOX11 belongs to the SOX gene family subgroup C encoding transcription factors, critical in embryonic differentiation, neuronal survival and cellular differentiation. The oncogenic potential of SOX11 in MCL has been demonstrated in xenograft models, but the full mechanisms involved in promoting its function are still not well understood.…”

Validation of the MCL35 gene expression proliferation assay in randomized trials of the European Mantle Cell Lymphoma Network

“…), if the tumour cell content is sufficient (≥60%). This assay is not aimed for MCL patients that show a leukaemic, non-nodal disease, but a new assay to classify patients with leukaemic MCL into risk groups was very recently published (Clot et al, 2018). In addition, the MCL35 assay failed technically, partly due to poor fixation of the FFPE sample but in the majority of cases for unknown reasons in approximately 10% of these archival MCL specimens that otherwise fulfilled the inclusion criteria.…”