IDIBAPS Mantle Cell Lymphoma 2013 (Beà)

Overview

Whole-genome (n=4) and whole-exome (n=29) sequencing study of mantle cell lymphoma (MCL) tumor/normal pairs plus six MCL cell lines, with targeted validation in an independent cohort of 172 MCL patients. Led by Beà, Campo, and colleagues at IDIBAPS/Hospital Clínic, Barcelona, and published in PNAS 2013. The study identified 25 significantly mutated genes, established NOTCH2 as an independent prognostic factor, described novel mutations in chromatin modifiers (NSD2, KMT2D, MEF2B), and documented subclonal heterogeneity and clonal evolution at progression/relapse. The cBioPortal study identifier is mcl_idibips_2013. Raw sequencing data deposited under EGA accession EGAS00001000510; expression/SNP arrays under GEO GSE46969 / GSE36000.

Composition

  • Cancer type: MCL — mantle cell lymphoma.
  • Discovery cohort: 4 WGS + 29 WES tumor/normal pairs (primary MCL); 6 MCL cell lines (WES).
  • Validation cohort: 172 independent MCL patients (targeted/Sanger sequencing of recurrently mutated genes).
  • Total: ~201 MCL patients profiled across the full study (29 WES primaries + 172 validation).
  • Sequential/paired samples: 8 cases with paired WGS/WES biopsies (simultaneous anatomical sites or diagnosis/relapse); 19 additional cases with paired targeted sequencing.
  • WES median: 20 protein-coding mutations per case (range 8–47); WGS ~3,700 somatic mutations per tumor (1.2/Mb). PMID:24145436

Assays / panels (linked)

Papers using this cohort

  • PMID:24145436 — Beà S et al., “Landscape of somatic mutations and clonal evolution in mantle cell lymphoma”, PNAS 2013.

Notable findings derived from this cohort

  • 25 significantly mutated genes identified by WES; all 29 primary tumors carried ≥1 mutation in this set. Mutational burden (mean 11±4 vs 25±11, P=3.4×10⁻⁵) and CNA burden (mean 2±3 vs 12±9, P=0.001) were significantly lower in 5 patients with indolent, untreated disease. PMID:24145436
  • NOTCH2 PEST-truncating mutations in 9/172 (5.2%) MCL confer dismal prognosis (3-year OS 0% vs 62%, P=2.5×10⁻⁴) and are an independent OS risk factor (HR 3.5; 95% CI 1.3–9.5; P=0.017); mutually exclusive with NOTCH1 mutations (8/172, 4.6%). PMID:24145436
  • NSD2 (WHSC1/MMSET) mutated in 13/130 (10%) MCL — first description in lymphoma; NSD2-mutated MCL transcriptionally phenocopies t(4;14) plasma-cell myeloma. PMID:24145436
  • BIRC3 inactivating mutations in 11/173 (6.4%) MCL; tightly co-occurring with 11q22.2 deletion (10/11 mutated cases, P=1.1×10⁻⁴); acquired post-treatment in 2 relapse cases. PMID:24145436
  • Kataegis foci (regional hypermutation) observed in 3/4 WGS cases, clustering around the t(11;14) 11q13 breakpoint and Ig loci; stable in sequential samples — suggesting kataegis is an early, stable MCL event. PMID:24145436
  • SOX11 expression partitions the mutation landscape: ATM/NSD2/KMT2D/MEF2B mutations enriched in SOX11-positive IGHV-unmutated MCL; CCND1/TLR2 mutations enriched in SOX11-negative IGHV-mutated MCL. PMID:24145436
  • Clonal evolution documented at progression: one case gained 20 CNAs and chromothripsis on chr4/12; another showed subclone replacement after chemotherapy with loss of 11 initial mutations and new driver acquisition. PMID:24145436

Sources

  • cBioPortal study: mcl_idibips_2013
  • PMID:24145436 — primary publication
  • EGA: EGAS00001000510 (sequencing); GEO: GSE46969 (SNP6.0), GSE36000 (HU133+2.0)

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