Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features

Abstract

Mantle cell lymphoma (MCL) is a heterogeneous disease with most patients following an aggressive clinical course, whereas others having an indolent behavior. We conducted an integrative and multidisciplinary analysis of 177 MCL to determine whether the immunogenetic features of the clonotypic B-cell receptors (BcR) may identify different subsets of tumors. Truly unmutated (100% identity) IGHV genes were found in 24% cases, 40% were minimally/borderline mutated (99.9%-97%), 19% significantly mutated (96.9%-95%), and 17% hypermutated (<95%). Tumors with high or low mutational load used different IGHV genes, and their gene expression profiles were also different for several gene pathways. A gene set enrichment analysis showed that MCL with high and low IGHV mutations were enriched in memory and naive B-cell signatures, respectively. Furthermore, the highly mutated tumors had less genomic complexity, were preferentially SOX11-negative, and showed more frequent nonnodal disease. The best cut-off of germline identity of IGHV genes to predict survival was 97%. Patients with high and low mutational load had significant different outcome with 5-year overall survival (OS) of 59% and 40%, respectively (P = 0.004). Nodal presentation and SOX11 expression also predicted for poor OS. In a multivariate analysis, IGHV gene status and SOX11 expression were independent risk factors. In conclusion, these observations suggest the idea that MCL with mutated IGHV, SOX11-negativity, and nonnodal presentation correspond to a subtype of the disease with more indolent behavior.

Figure 1

Distribution of rearrangements of the six more frequent IGHV genes in subgroups of MCL with different mutational status.

Figure 2

IGHV mutational load according to SOX11 expression. A, Box plot of the percentage of IGHV identity in MCL cases negative and positive for SOX11 expression. B, Distribution of the cases according to four subgroups of IGHV gene mutational status and SOX11 expression.

Figure 3

Characterization of MCL cases according to their distinct genetic and molecular features. The 101 cases in which SNP-array analyses were performed are represented. In the upper panel the number of genomic alterations (bar plots) and the % of identity of IGHV genes (from left to right in decreasing order).

Figure 4

A, Differences in the gene expression profile between U-MCL and M-MCL. Heatmap displaying the main pathways enriched among the genes differentially expressed. B, Enrichment plots obtained from GSEA. Significant enrichment of the naïve B-cell gene set in the U-MCL/SOX11-possitive and significant enrichment of the memory B-cell gene set in M-MCL/SOX11-negative.

Figure 5

Kaplan-Meier estimates of OS for MCL patients according to IGHV gene mutational status and SOX11 expression. A, OS for the four different subgroups of IGHV identity. HM and SM have better OS (5-year OS 61%, 95% confidence interval [CI], 35–87 and 5-year OS 55%, 95% CI, 29–81, respectively) compared to MBM (5-year OS 14%, 95% CI, 34–62) and TU (5-year OS 18%, 95% CI, 7–43). B, OS subgroups of MCL with <97% (Unmutated U-MCL) and ≥97% (Mutated M-MCL) identity. M-MCL showed better OS (5-year OS 59%, 95% CI, 41–77) than U-MCL (5-year OS 40%, 95% CI, 28–52). C, OS according to IGHV gene mutational status and SOX11 expression. M-MCL SOX11-negative showed a better OS (5-year OS 73%, 95% CI, 52–94) than the other groups (M-MCL SOX11-pos: 5-year OS 42%, 95% CI, 12–72; U-MCL SOX11-neg: 5-year OS 48%, 95% CI, 13–83; U-MCL SOX11-pos: 5-year OS 38%, 95% CI, 26–50). D, OS of the M-MCL SOX11-negative patients with 17p/TP53 alterations showed a worse OS (5-year OS 36%, 95% CI, 0–76) than patients without 17p/TP53 alterations (5-year OS 92%, 95% CI, 77–100).