Acquired Genomic Copy Number Aberrations and Survival in Adult Acute Myelogenous Leukemia

Purpose: Genomic aberrations are of dominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotyping-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of karyotyping is the low sensitivity of this method to detect genomic abnormalities in the sub-megabase (Mb) to ~5 Mb range, and it is currently unclear whether overcoming this limitation with array-based high-resolution karyotyping could be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the risks inherent in conventional karyotyping-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. Here, we have analyzed FACS-sorted AML blast-derived and paired buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and LOH using Affymetrix SNP 6.0 arrays, and we have correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Conclusions: Using multivariate analyses, we found that having ≥2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age and karyotype-based risk. Finally, we identified an independent negative prognostic impact of p53 mutations, 17p-LOH or both on survival in AML. Experimental design: We analyzed DNA from highly purified AML blasts and paired buccal cells from 114 patients using ultra-high density Affymetrix SNP 6.0 array-based genomic profiling. Patients 1 and 211 lack a correlate normal sample.