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2018-01-18T10:05:56.000Z

Clinical impact and dynamic changes of cohesin gene mutations in de novo AML

Jan 18, 2018
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Novel mutations in the genes of the cohesin complex (a structure that is essential for cell division) including SMC1A, SMC3, RAD21, STAG2, and STAG1 occur in approximately 13% of Acute Myeloid Leukemia (AML) patients.1 There is a paucity of studies that have explored the clinical and prognostic significance and dynamic changes in patients with de novo AML and the limited data on this remain controversial.

Cheng-Hong Tsai from the National Taiwan University Hospital, Taipei, Taiwan, and colleagues investigated the clinical, biological and prognostic implications of cohesin gene mutations in patients with de novo AML during the clinical course. The results from the study were reported in a correspondence to the editor of Blood Cancer Journal.2

In this study by Tsai et al., samples from 391 newly diagnosed de novo non-M3 AML patients were first examined with targeted Next Generation Sequencing (NGS) in order to determine cohesin mutations and their clinico-biological associations. Additionally, survival analyses were performed in patients (n = 286) who received standard chemotherapy. The median follow-up time was 53.0 months (range, 0.1–160).

Key findings:

  • Thirty-seven patients (9.5%) had cohesin gene mutations, most commonly RAD21 (3.8%), STAG2 (3.1%), and SMC1A (2.0%)
  • Of the 37 patients with cohesin gene mutation, 81.1% had at least one other gene mutation
    • Most common co-occurring mutations include FLT3/ITD (21.6%) and NPM1 (21.6%)
    • TP53 mutations were not found
    • Compared to other cohesin gene mutations, STAG2 mutations co-occurred:
      • with RUNX1 mutations, 27.3% vs 0%, P = 0.023,
      • with ASXL1 mutations, 25.0% vs 4.0%, P = 0.084
      • less frequently with NPM1 mutations, 0% vs 32.0%, P = 0.036
    • Overall Survival (OS) in patients with (n = 26) or without (n = 260) cohesin gene mutation: not reached vs 20.0 ± 2.3 months, P = 0.036
    • Disease Free Survival (DFS) in patients with (n = 23) or without (n = 197) cohesin gene mutation: 24.5 ± 0.0 vs 9.0 ± 0.8 months, P = 0.038
      • Cohesin gene mutations were independent favorable factors for OS (Relative Risk [RR] = 0.487, P = 0.028) and DFS (RR = 0.489, P = 0.047)

In order to assess dynamic changes of cohesin and co-occurring gene mutations, the authors using targeted NGS analyzed 386 samples from 116 patients with (n = 19) or without (n = 97) cohesin gene mutations at baseline.

  • Seventeen patients harboring cohesin mutations lost the original mutations at Complete Remission (CR)
  • Two patients, harboring cohesin mutations had detectable mutations at CR and eventually relapsed
    • DNMT3A mutations remained detectable in four patients who also harbored IDH1, U2AF1, NPM1 or NRAS mutations
  • None of the patients (n = 97) without cohesin gene mutations at baseline acquired mutation at relapse

Using genome-wide mRNA expression profiling, Tsai et al. identified 162 genes that were differentially expressed between cohesin mutated and cohesin wild-type patients. Gene set enrichment analysis revealed that these genes were significantly associated with differentiation, proliferation and apoptosis of blood cells thus indicating that cohesin mutated genes exhibit biological functions.

In summary, this is the first study to report on the dynamic changes of cohesin gene mutations during the clinical course in de novo AML. “Cohesin genes were recurrent in de novo AML” and had favorable impact on OS and DFS. Additionally, “sequential analyses showed cohesin gene mutations might be lost during disease evolution in de novo AML patients, but none of the patients without the mutation acquired a novel one during the clinical course” signifying that the “mutations played little role in the progression of AML”.

The authors concluded by stating that the findings of their study should be confirmed in prospective studies with larger cohorts.

  1. Thol F. et al. Mutations in the cohesin complex in acute myeloid leukemia: clinical and prognostic implications. Blood. 2014 Feb 6; 123(6): 914–20. DOI: 10.1182/blood-2013-07-518746. Epub 2013 Dec 13.
  2. Tsai C.H. et al. Prognostic impacts and dynamic changes of cohesin complex gene mutations in de novo acute myeloid leukemia. Blood Cancer Journal. 2017 Dec 29. DOI: 10.1038/s41408-017-0022-y

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