PCNSL Mayo Clinic 2015 (Chapuy et al.)

Overview

Comprehensive genomic characterization of 19 immunocompetent primary central nervous system lymphoma (PCNSL) cases from the Mayo Clinic Tumor Registry and the University of Virginia. Published 2015 (PMID:25991819). The study combined array-CGH, whole-exome sequencing, mate-pair sequencing, targeted sequencing, Sanger validation, and FISH to define the genomic landscape of PCNSL versus systemic DLBCL. aCGH microarray data deposited in GEO under accession GSE28952.

Composition

  • N = 19 immunocompetent PCNSL patients (HIV−, EBV−), newly diagnosed, disease confined to the CNS.
  • Cancer type: PCNSL; comparisons made throughout to systemic DLBCLNOS.
  • Tissue source: frozen tissue (7 cases) or FFPE (12 cases); 3 frozen samples required whole-genome amplification due to low yield.
  • Matched normal: 9 of 19 biopsies provided tumor-free tissue for matched-normal validation sequencing.

Assays / panels (linked)

  • array-cgh-agilent-1m — 18 cases; Human Genome 244A + Sureprint G3 (Agilent); CNA calling via Nexus RANK segmentation; CNVs filtered using TCAG database plus 10 in-house HapMap controls.
  • whole-exome-seq — 10 cases; SureSelect 50 Mb capture; 100 bp paired-end on HiSeq2000; mean 65.6M mapped reads, median 80% of exome at ≥30× coverage. SNVs called with SomaticSniper; indels with gatk-somatic-indel-detector; annotated by snpEFF/PolyPhen-2 via TREAT workflow.
  • mate-pair-seq — structural rearrangement detection.
  • targeted-dna-seq — Ion Torrent PGM for MYD88 coding regions (~2,005× average depth); Sanger sequencing for CARD11/CD79B/PRKCD/TNFAIP3 variants.
  • fish — interphase FISH for IGH-BCL6, PRKCD, and TOX rearrangements.

Papers using this cohort

  • PMID:25991819 — Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphoma; primary discovery study for this cohort.

Notable findings derived from this cohort

  • BCR/TLR/NF-κB pathway altered in >90% of PCNSL when integrating mutation and CNA data. PMID:25991819
  • MYD88 activating mutations in 79% of cases (predominantly L265P) — ~2× the prevalence in nodal ABC-DLBCL — making MYD88-dependent signaling a particularly attractive PCNSL target. PMID:25991819
  • CDKN2A/CDKN2B 9p21.3 deletion in 83% of cases (homozygous in 55%), making it the most common CNA in the cohort. PMID:25991819
  • PCNSL-specific biallelic inactivation of PRKCD (splice-donor mutations + missense) and homozygous deletion of TOX (8q12) — neither event reported recurrently in systemic DLBCL. PMID:25991819
  • PRDM1 6q21 deletion (55% of cases) associated with shorter overall survival (log-rank P=0.001) in univariate analysis. PMID:25991819

Sources

  • cBioPortal study: pcnsl_mayo_2015
  • GEO: GSE28952 (aCGH microarray data)

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