PROGNOSTIC SIGNIFICANCE OF GENETIC ABERRATIONS IN SECONDARY ACUTE MYELOID LEUKEMIA

Sborník

Background. Chronic myeloproliferative neoplasms and myelodysplastic syndromes can evolve to secondary acute myeloid leukemia (sAML). It has been shown that sAML can arise either on the background of the chronic phase founder clone, or as an independent event, resembling de novo AML (dnAML). The leukemogenesis in sAML is poorly understood and these patients have poor prognosis. Aims. The main aim of the study was to compare genetic lesions in sAML and dnAML patients, and identify those with the most prominent impact on the overall survival (OS). Furthermore, we aimed to analyze the interplay of genetic aberrations in different genomic regions and their potential use in patient stratification. Methods. High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix SNP 6.0 arrays. TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1 and FLT3 genes were analyzed individually for mutations in all patients. OS comparisons were performed using the log-rank test, and multivariate survival analysis using Cox’s regression model. Mutual information and interaction information analysis were performed using the R package “infotheo”. Results. Patients with sAML showed higher karyotype complexity than dnAML (P<0.001), and more rarely a normal karyotype (P=0.002). We identified a total of 669 deletions, gains and acquired uniparental disomies (UPD). There were 36 recurrent aberrations (>5 events), most of which associated with sAML. High number of events allowed fine mapping (<1Mb) of target genes, such as JARID2, IKZF1, NF1. Mutations in TP53, 9pUPD, and del7q (harboring CUX1) were significantly associated with sAML, while NPM1 and FLT3 mutations were significantly associated with dnAML. Mutations in IDH1/2 were mutually exclusive with TP53 and NRAS mutations. Patients with sAML had worse 3-year OS rate (11.3%±4.9%) compared to dnAML (35.2%±5.3%; P=0.003). We analyzed the influence of features not associated with chronic phase or dnAML on OS of sAML patients. SAML patients with TP53 mutations showed a significantly shorter OS (1.8 months, 95%CI, 0.8-2.8) compared to patients with wtTP53 (5.6 months, 95%CI, 1.5-9.7). Patients carrying TP53 mutations demonstrated a lower 1-year OS rate then those with wtTP53 (7.1%±6.9% vs. 32.9%±7.1%; P=0.002). Complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on survival of sAML patients. Multivariate analysis confirmed that mutation in TP53 was the only independent adverse prognostic factor for OS (hazard ratio 2.41; 95%CI, 1.20-4.82; P=0.013) in sAML.The mutual information analysis showed that del5q and TP53 mutations, del12p (ETV6) and del5q, 11q gains and del17q, associate with respect to diagnosis. The negative interaction information analysis, indicating exclusivity to sAML, showed association for del5q and 9pUPD, del5q and TP53 mutations, as well as del20q and del4q (TET2). Conclusions. Our data suggests that distinct genetic lesions drive leukemogenesis in sAML, compared to dnAML. High karyotype complexity of sAML patients does not influence their OS, and indicates the presence of mainly passenger aberrations. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. The mutual information and interaction analysis identified several potential markers for genetic stratification of patients with AML.

Haematologica, 2012; 97(s1):  152