Acute Myeloid Leukemia — TCGA (2013)

Overview

The Cancer Genome Atlas comprehensive genomic and epigenomic characterization of 200 clinically annotated adult de novo AML cases, published in NEJM 2013. Samples drawn from a single-institution Washington University tissue-banking protocol (Nov 2001–Mar 2010), selected to reflect a real-world distribution of FAB and cytogenetic subtypes. PMID:23634996

Composition

  • 200 adult de novo AML cases with matched normal (peripheral blood or skin); selected to reflect a real-world distribution of FAB subtypes and cytogenetic risk groups. PMID:23634996
  • 50 cases profiled by whole-genome sequencing (mean coverage 30.54×); 150 by whole-exome sequencing (mean coverage 167.50×); all somatic variants validated by hybridization-capture deep digital sequencing. PMID:23634996
  • Multi-platform profiling: RNA-seq (179 samples), microRNA-seq (194 samples), Affymetrix U133 Plus 2 expression (197 samples), Illumina HumanMethylation450 arrays (192 samples), Affymetrix SNP 6.0 copy-number arrays (all 200 patients with matched normal skin). PMID:23634996

Assays / panels (linked)

Papers using this cohort

  • PMID:23634996 — The Cancer Genome Atlas Research Network, “Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia,” N Engl J Med 2013.
  • PMID:27959731 — Welch et al., N Engl J Med 2016: Used as comparator to benchmark TP53 mutation spectrum and methylation patterns from the WashU decitabine trial (mnm_washu_2016); no TP53-driven methylation signature identifiable in either dataset.

Notable findings derived from this cohort

  • Adult AML genomes are mutation-sparse (mean 13 coding mutations per sample); 23 significantly mutated genes at FDR<0.05 including DNMT3A, FLT3, NPM1, IDH1, IDH2, CEBPA, U2AF1, EZH2, SMC1A, and SMC3. PMID:23634996
  • Nearly every sample (199/200) harbored at least one driver in one of nine functional categories: transcription-factor fusions (18%), NPM1 (27%), tumor suppressors (16%), DNA-methylation genes (44%), activated signaling (59%), chromatin modifiers (30%), myeloid transcription factors (22%), cohesin-complex (13%), and spliceosome (14%). PMID:23634996
  • Novel co-occurring triplet of NPM1 + DNMT3A + FLT3 mutations defines a distinct epigenetic AML subtype by mRNA, miRNA, and DNA-methylation clustering, with extensive methylation loss. PMID:23634996
  • IDH1/IDH2-mutant samples showed extensive methylation gains; KMT2A fusions and the triple-mutant group showed extensive methylation loss; 160,519 CpG loci differentially methylated (67% gain, 33% loss). PMID:23634996
  • Deep digital sequencing enabled VAF-based clonal architecture reconstruction: >50% of WGS tumors had a founding clone plus ≥1 subclone; minimal aneuploidy (median 1 somatic SCNV per genome) and no chromothripsis. PMID:23634996
  • 118 gene fusions identified in 80/179 samples by de novo RNA-seq assembly; recurrent in-frame fusions included PML–RARA, MYH11–CBFB, RUNX1–RUNX1T1, and NUP98–NSD1. PMID:23634996
  • Used as an independent validation cohort to replicate 11 AML genomic subgroups (chromatin–spliceosome, TP53–aneuploidy, IDH2 R172, etc.) identified in 1540 AMLSG trial patients; subgroup structure and prognostic associations were confirmed in this TCGA AML dataset. PMID:27276561
  • TP53 mutation spectrum (missense-dominant, hotspot distribution) in the WashU decitabine trial cohort was indistinguishable from that in this TCGA AML dataset; no TP53-driven CpG methylation signature was detectable in either cohort, arguing against a methylation-based mechanism for TP53-decitabine sensitivity. PMID:27959731

Sources

  • DOI: 10.1056/NEJMoa1301689
  • Washington University tissue-banking protocol (Nov 2001–Mar 2010)

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