Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis.
Blood, 2014/8/21;124(8):1304-11.
Herold T[1], Metzeler KH[1], Vosberg S[1], Hartmann L[1], Röllig C[2], Stölzel F[3], Schneider S[4], Hubmann M[5], Zellmeier E[4], Ksienzyk B[4], Jurinovic V[6], Pasalic Z[4], Kakadia PM[7], Dufour A[4], Graf A[8], Krebs S[8], Blum H[8], Sauerland MC[9], Büchner T[10], Berdel WE[10], Woermann BJ[11], Bornhäuser M[2], Ehninger G[2], Mansmann U[12], Hiddemann W[1], Bohlander SK[13], Spiekermann K[1], Greif PA[1]
Affiliations
PMID: 24923295DOI: 10.1182/blood-2013-12-540716
Impact factor: 25.476
Abstract
In acute myeloid leukemia (AML), isolated trisomy 13 (AML+13) is a rare chromosomal abnormality whose prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and performed exome sequencing, targeted candidate gene sequencing and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN Intermediate-II patients (n=855) (median RFS, 7.8 vs 14.1 months, P = .006; median OS 9.3 vs. 14.8 months, P = .004). Besides the known high frequency of RUNX1 mutations (75%), we identified mutations in spliceosome components in 88%, including SRSF2 codon 95 mutations in 81%. Recurring mutations were detected in ASXL1 (44%) and BCOR (25%). Two patients carried mutations in CEBPZ, suggesting that CEBPZ is a novel recurrently mutated gene in AML. Gene expression analysis revealed a homogeneous expression profile including upregulation of FOXO1 and FLT3 and downregulation of SPRY2. This is the most comprehensive clinical and biological characterization of AML+13 to date, and reveals a striking clustering of lesions in a few genes, defining AML+13 as a genetically homogeneous subgroup with alterations in a few critical cellular pathways. Clinicaltrials.gov identifiers: AMLCG-1999: NCT00266136; AML96: NCT00180115; AML2003: NCT00180102; and AML60+: NCT00893373.
MeSH terms
Adolescent; Adult; Aged; Aged, 80 and over; Chromosomes, Human, Pair 13; Disease-Free Survival; Female; Gene Expression Regulation, Leukemic; Germany; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Proteins; Survival Rate; Trisomy; Up-Regulation
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