Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality

Abstract

Monosomy of chromosome 7 is the most frequent autosomal monosomy in acute myeloid leukemia (AML), where it associates with poor clinical outcomes. However, molecular features associated with this sole monosomy subtype (-7 AML), which may give insights into the basis for its poor prognosis, have not been characterized. In this study, we analyzed 36 cases of -7 AML for mutations in 81 leukemia/cancer-associated genes using a customized targeted next-generation sequencing panel (Miseq). Global gene and miRNA expression profiles were also determined using paired RNA and small RNA sequencing data. Notably, gene mutations were detected in all the major AML-associated functional groups, which include activated signaling, chromatin remodeling, cohesin complex, methylation, NPM1, spliceosome, transcription factors, and tumor suppressors. Gene mutations in the chromatin remodeling groups were relatively more frequent in patients <60 years of age, who also had less mutations in the methylation and spliceosome groups compared with patients ≥60 years of age. Novel recurrent mutational events in AML were identified in the SMARCA2 gene. In patients ≥60 years of age, the presence of spliceosome mutations associated with a lower complete remission rate (P = 0.03). RNA sequencing revealed distinct gene and miRNA expression patterns between the sole -7 and non -7 AML cases, with reduced expression, as expected, of many genes and miRNAs mapped to chromosome 7, and overexpression of ID1, MECOM, and PTPRM, among others. Overall, our findings illuminate a number of molecular features of the underlying aggressive pathobiology in -7 AML patients. Cancer Res; 77(1); 207-18. ©2016 AACR.

Figure 1

Oncoprint of mutations found in functional groups (listed by descending frequencies; upper panel) and single gene mutations (lower panel) in patients with AML and sole -7. Patients (one per column) are depicted separately by age group (<60 years, green and ≥60 years, orange). Black highlights in the upper panels indicate the presence of ≥1 mutation in ≥1 gene assigned to the functional group. The lower panels list the respective gene mutations. Red highlights indicate the presence of a gene mutation, grey highlights indicate wild-type status (see Patients and Methods for details), white highlights indicate that the mutation status is not available (n.a.). s-AML denotes secondary AML; t-AML, therapy-related AML.

Figure 2

Heatmap depicting the differential miR expression of AML patients with sole -7 (n=31, indicated by red bars) and AML patients with other cytogenetics of the TCGA AML cohort¹⁹ (excluding patients with chromosome 7 abnormalities and/or complex karyotype, n=136). Lower expression is shown in green, while higher expression is shown in red. The derived miR-expression signature comprised six miRs downregulated and 10 miRs upregulated in sole -7 AML, with an adjusted P-value of <0.001. The significantly down- and upregulated miRs and the corresponding P-values and fold changes can be found in Supplementary Tables S5 and S6, respectively.