Chronic Lymphocytic Leukemia (Broad, Nature 2015)

Overview

The cll_broad_2015 dataset comprises whole-exome sequencing of 538 chronic lymphocytic leukemia (CLL) samples with matched germline DNA, published by Landau et al. in Nature (2015). The cohort combines the phase III CLL8 trial prospective sub-cohort (n=278 pre-treatment samples, median >6 years follow-up, randomized between FC and FCR), two prior non-overlapping CLL WES cohorts (n=260), and matched relapse exomes from 59 CLL8 subjects. Mean exome read depth was 95.0× (tumor) / 95.7× (normal). CLL8 WES data are deposited in dbGaP (phs000922.v1.p1).

Composition

  • 538 CLLSLL whole-exomes with matched germline DNA.
  • Prospective sub-cohort: 278 pre-treatment samples from the CLL8 phase III trial (FC vs FCR randomization).
  • Longitudinal sub-cohort: 59 matched pre-treatment/relapse pairs from CLL8 subjects.
  • Matched RNA-seq in 156 cases for orthogonal validation.
  • Reference genome: hg19.

Assays / panels (linked)

Papers using this cohort

  • PMID:26466571 — Landau et al. 2015, Nature — “Mutations driving CLL and their evolution in progression and relapse.”

Notable findings derived from this cohort

  • 44 recurrently mutated CLL driver genes identified (18 previously reported + 26 novel, including RPS15 and IKZF3); 91.1% of CLLs carry at least one driver event PMID:26466571.
  • In the CLL8 prospective sub-cohort, mutated TP53, SF3B1, and the novel driver RPS15 each independently predicted shorter progression-free survival (PFS); any pre-treatment subclonal driver predicted shorter PFS (HR 1.6, 95% CI 1.2–2.2, P=0.004) PMID:26466571.
  • Non-canonical BRAF mutations in CLL cluster in the kinase activation segment rather than at V600E, implying distinct mechanism and reduced sensitivity to V600E-selective inhibitors PMID:26466571.
  • Large clonal shifts observed in 57/59 (97%) paired pre-treatment/relapse exomes; eventual relapse clone detectable pre-treatment in 30% of cases by WES, rising further with targeted deep sequencing PMID:26466571.
  • sCNVs are the earliest driver events; del(13q) and tri(12) are mutually exclusive entry points converging on del(11q); copy loss precedes sSNV/sINDEL hits in biallelic ATM and BIRC3 inactivation PMID:26466571.

Sources

  • Landau DA et al. “Mutations driving CLL and their evolution in progression and relapse.” Nature. 2015;526(7574):525-530. PMID:26466571. DOI: 10.1038/nature15395.

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