General AML|DNMT3A|RUNX1

Mutational landscape of AML patients with monosomy 7

The most common chromosomal abnormality observed in high-risk Acute Myeloid Leukemia (AML) patients is the loss of chromosome 7 (sole -7). Sole -7 in AML patients is associated with poor prognosis, including low initial Complete Remission (CR) rates, short remissions, and inferior survival compared to patients in other cytogenetic groups. Defining the so far uncharacterized molecular features associated with sole -7 might provide insights into basis for the associated poor prognosis.

Ann-Kathrin Eisfeld from the Ohio State University Comprehensive Cancer Centre, Columbus, Ohio, and colleagues published data, which characterized the mutational landscape and microRNA (miR) gene expression profiles of 36 adult AML patients with -7 as a sole cytogenetic abnormality. 81 leukemia/cancer-associated genes were tested in AML patients with sole -7. Patients were split in two cohorts: younger patients (<60; median age = 52) and older patients (≥60; median age = 68)

The results were first published ahead of print in Cancer Research in October 2016.  

The key results of the study:
  • In all sole-7 patients, Disease Free Survival (DFS), Overall Survival (OS), and CR were 8.4 months, 9.2 months, and 42% (n=15), respectively
  • No significant difference in CR and OS between patients <60 and patients ≥60
  • In all sole-7 patients, most frequently mutated genes were RUNX1 (n =10), ASXL1 (n = 9), NRAS (n = 9), TET2 (n = 9), DNMT3A (n = 8), and SRSF2 (n = 8)
  • Single SMARCA2 mutations occurred in four patients and two SMARCA2 mutations occurred in two patients
  • Gene mutations were detected in all the major AML-associated functional groups, including mutations in genes involved in methylation 53% (n=19), genes leading to activated signaling 50% (n=18), genes involved in chromatin modelling 42% (n=15), spliceosome 39%( n=14), and transcription factors 36% (n=13)
  • Only patients ≥60 had TET2 mutations; P = 0.03
  • Patients <60 harbored more mutations in chromatin remodeling genes compared to patients ≥60; 64% vs 32%
  • Patients ≥60 harbored more mutations in methylation genes compared to patients <60; 64% vs 27%
  • Patients ≥60 harbored more mutations in spliceosome genes compared to patients <60; 48% vs 18%
  • 88% of patients ≥60  harbored at least one mutation in genes involved in methylation vs 55% of patients <60; P = 0.04
  • CR in patients ≥60 with sole -7 harboring a mutation in a spliceosome gene vs without spliceosome mutation; 17% vs 62%, P = 0.03
  • Most frequently upregulated genes in sole -7 patients included Protein Tyrosine Phosphatase Receptor Type M gene (PTPRM), ID1, and MECOM
  • Compared to non-sole -7 AML, sole -7 AML patients had six significantly  downregulated miRs  and 10 significantly upregulated miRs

In summation, this is a small sample size, yet it also the largest study to date to conduct an analysis of this nature. The results have provided useful insights, a relatively large number of gene mutations were detected in AML patients with sole -7, thus indicating that sole -7 AML is molecularly heterogeneous. Additionally, mutation patterns observed were partly due to the age of the patients. Furthermore, it was observed that older patients harboring more spliceosome mutations had reduced CR rates. The authors suggest that this finding provides a rationale for testing spliceosome mutations at diagnosis in older sole -7 AML patients.

The authors concluded by stating that their data identified age-associated gene mutations patterns, deregulated genes, and micro-RNA profiles, thus providing a broad insight on the molecular features of the aggressive pathobiology in AML patients with sole -7.  

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.

References
  1. Eisfeld A.K. et al. Mutational Landscape and Gene Expression Patterns in Adult Acute Myeloid Leukemias with Monosomy 7 as a Sole Abnormality. Cancer Research. 2017 Jan 1; 77(1): 207–218. DOI: 10.1158/0009-5472.CAN-16-1386. Epub 2016 Oct 26.