Mantle Cell Lymphoma (MCL)

Overview

Mantle Cell Lymphoma (MCL) is a mature B-cell neoplasm within the Lymphoid tissue branch of OncoTree, sitting under the Mature B-Cell Neoplasms (MBN) parent node. It is defined by overexpression of cyclin D1 driven by the t(11;14)(q13;q32) translocation juxtaposing CCND1 with the IGH locus. MCL is biologically heterogeneous: SOX11-positive tumors with unmutated IGHV present an aggressive clinical course, while SOX11-negative / IGHV-mutated cases are typically more indolent.

Cohorts in the corpus

  • mcl_idibips_2013 — WGS (n=4), WES (n=29 primaries + 6 cell lines), and targeted validation in 172 MCL patients; SNP 6.0 arrays and gene-expression profiling (HU133+2.0); deposited as EGA EGAS00001000510 and GEO GSE46969/GSE36000 PMID:24145436.

Recurrent alterations

  • WES/WGS of 33 MCL tumors identified 25 significantly mutated genes; all 29 primary tumors harbored at least one; novel drivers include NSD2 (WHSC1), KMT2D (MLL2), MEF2B (chromatin modifiers), BIRC3, TLR2, and NOTCH2 alongside known drivers ATM, CCND1, and TP53 PMID:24145436.
  • ATM — truncating/functional-domain mutations in 41% of WES cases; significantly enriched in SOX11-positive MCL (55% vs 0% in SOX11-negative); often biallelic via 11q deletion; an early/clonal event PMID:24145436.
  • CCND1 — exon-1 mutations in 35% of WES cases; enriched in SOX11-negative (86% vs 18%) and IGHV-mutated (58% vs 19%) tumors, consistent with germinal-center acquisition PMID:24145436.
  • TP53 — mutations in 22% of the total cohort (42/192); associated with 17p allelic loss; independent OS risk factor (HR 2.4; 95% CI 1.4–4.2; P=0.003) PMID:24145436.
  • NSD2 (WHSC1/MMSET) — recurrent missense p.E1099K and p.T1150A in 10% (13/130) of MCL; restricted to SOX11-positive tumors; transcriptionally phenocopies t(4;14) plasma-cell myeloma PMID:24145436.
  • NOTCH1 / NOTCH2 — PEST-truncating mutations in 4.6% and 5.2% of MCL respectively; mutually exclusive in 15/16 mutated cases; combined NOTCH1/2 mutations mark an aggressive subset (3-y OS 24% vs 63%, P=3.4×10⁻⁴); NOTCH2 mutation is an independent OS risk factor (HR 3.5, P=0.017) PMID:24145436.
  • BIRC3 — inactivating mutations in 6.4% (11/173); tightly co-occurs with 11q22.2 deletion; can be acquired post-treatment PMID:24145436.
  • CDKN2A — only gene with recurrent homozygous deletions in MCL; no somatic point mutations detected PMID:24145436.
  • Mutational burden stratifies clinical course: indolent MCL (no treatment required) carries significantly fewer protein-coding mutations (mean 11 vs 25, P=3.4×10⁻⁵) and fewer CNAs (mean 2 vs 12, P=0.001) than treatment-requiring cases PMID:24145436.

Subtypes

  • SOX11-positive / IGHV-unmutated MCL — aggressive subtype; enriched for ATM, NSD2, KMT2D, MEF2B mutations; higher CNA burden; typically treatment-requiring.
  • SOX11-negative / IGHV-mutated MCL — indolent subtype; enriched for CCND1 exon-1 and TLR2 mutations; lower CNA burden; 5 patients in the WES cohort required no treatment over median 55-month follow-up PMID:24145436.
  • Blastoid/pleomorphic MCL — aggressive morphology enriched for NOTCH1/2 mutations; dismal 3-year OS of 0% for NOTCH2-mutant cases PMID:24145436.

Therapeutic landscape

  • NOTCH pathway inhibition (e.g., γ-secretase inhibitors) is proposed as a strategy for the NOTCH1/2-mutated aggressive subset PMID:24145436.
  • Chemotherapy-driven clonal selection leads to emergence of new dominant subclones at relapse (including post-treatment BIRC3 mutation acquisition), supporting relapse-time genomic profiling to guide targeted therapy PMID:24145436.

Sources

  • PMID:24145436 — Beà et al. WGS/WES of 33 MCL tumors with targeted validation in 172 patients; identified 25 significantly mutated genes and characterized clonal evolution.

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