Chronic Lymphocytic Leukemia (Broad, Nature Genetics 2022)

Overview

Largest integrated CLL cohort to date, combining WES/WGS, RNA-seq, and DNA methylation data from 1,148 patients to build a “CLL map” of drivers, subtypes, and prognostic features PMID:35927489.

Composition

  • 1,148 patients (1,095 CLLSLL, 54 MBL); WES/WGS n=1,074 (984 WES, 177 WGS), RNA-seq n=712 (603 treatment-naive used for clustering), DNA methylation n=999 (450k array n=490, RRBS n=509) PMID:35927489.
  • Contexts: active surveillance (n=680), post-treatment (n=52), clinical trial enrollment (n=416; 371 treatment-naive, 45 relapsed/refractory) PMID:35927489.

Assays / panels (linked)

Papers using this cohort

  • PMID:35927489 — Knisbacher et al., Molecular map of CLL and its impact on outcome.

Notable findings derived from this cohort

  • 202 candidate genetic drivers nominated (109 novel); top drivers SF3B1 17.5%, NOTCH1 12.3%, ATM 11.2%, TP53 9.1%; 24.2% of patients carried at least one novel driver mutation PMID:35927489.
  • U-CLL harbors substantially more significant drivers than M-CLL (54 vs 25; ratio 2.16, Binomial p=0.0015); fraction of patients with no identifiable driver dropped to 3.8% (from 8.9% in prior work), concentrated in M-CLL PMID:35927489.
  • 8 robust RNA-seq expression clusters in treatment-naive patients serve as independent prognostic factors beyond IGHV/epitype; integrated genetic+epigenetic+transcriptomic outcome model built PMID:35927489.
  • In contemporary ibrutinib/venetoclax era, TP53 mutation in the absence of 17p deletion was not associated with adverse outcomes in U-CLL PMID:35927489.

Sources

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