Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically

Abstract

Complex karyotype (CK) with ≥ 3 abnormalities is detected in 10-12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q, and/or 17p chromosome arms. The presence of 5q, 7q, and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥ 3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥ 1 balanced abnormality in addition to ≥ 2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations. They were younger (P = 0.007), had higher WBC (P = 0.001) and percentages of marrow (P < 0.001) and blood (P = 0.006) blasts, higher complete remission rates (P = 0.02), and longer overall survival (P < 0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.

Figure 1.

Overview of the study design. AML denotes acute myeloid leukemia; CALGB, Cancer and Leukemia Group B; CK, complex karyotype; NGS, next-generation sequencing.

Figure 2.

Distribution of the combinations of TP53 mutations and 17p genomic rearrangements (determined using SNP arrays) in subsets of patients with acute myeloid leukemia (AML) and a complex karyotype (CK): (a) typical CK (n=69), (b) atypical CK (n=33), (c) CK with rare recurrent balanced chromosome abnormalities (n=9), (d) CK with unique balanced chromosome abnormalities (n=10). Dark blue color denotes patients with both TP53 mutation and 17p genomic rearrangement; lighter blue, patients with TP53 mutation and no 17p genomic rearrangement; light blue, patients with wild-type TP53 and 17p genomic rearrangement present, and red color indicates patients with wild-type TP53 and no 17p genomic rearrangement. All patients in the first three subsets combined, indicated by the various shades of blue, are considered to harbor an alteration of TP53 (i.e., TP53 mutation, deletion of 17p resulting in loss of TP53 locus and/or copy-neutral loss of heterozygosity encompassing TP53 locus). Typical CK-AML (a) clearly differs from atypical CK-AML (b) with regard to the frequency of TP53 alterations (88% vs 15%; P<0.001).

Figure 3.

Oncoprint of mutations detected in acute myeloid leukemia patients with atypical and those with typical complex karyotype (CK). Subsets identified within both atypical and typical CK are separated by thicker blue vertical lines. Each column represents an individual patient, and each row represents a single gene. The genes are clustered into the previously reported functional groups, with N* indicating “NPM1”. “CEBPA bi” indicates biallelic mutations of the CEBPA gene. Red color denotes gene mutation, darker grey, wild-type status of the gene, and lighter grey, mutation status not determined.

Figure 4.

Comparison of (a) disease-free survival and (b) overall survival of acute myeloid leukemia patients with typical and atypical complex karyotype (CK).