Serum levels of mature microRNAs in DICER1-mutated pleuropulmonary blastoma

M. J. Murray*, S. Bailey, K. L. Raby, H. K. Saini, L. De Kock, G. A.A. Burke, W. D. Foulkes, A. J. Enright, N. Coleman, M. Tischkowitz

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

DICER1 is a critical gene in the biogenesis of mature microRNAs, short non-coding RNAs that derive from either-3p or-5p precursor microRNA strands. Germline mutations of DICER1 are associated with a range of human malignancies, including pleuropulmonary blastoma (PPB). Additional somatic 'hotspot' mutations in the microRNA processing ribonuclease IIIb (RNase IIIb) domain of DICER1 are reported in cancer, and which affect microRNA biogenesis, resulting in a-3p mature microRNA strand bias. Here, in a germline (exon11 c.1806-1810insATTGA) DICER1-mutated PPB, we first confirmed the presence of an additional somatic RNase IIIb hotspot mutation (exon25 c.5425G4A [p.G1809R]) by conventional sequencing. Second, we investigated serum levels of mature microRNAs at the time of PPB diagnosis, and compared the findings with serum results from a comprehensive range of pediatric cancer patients and controls (n1/452). We identified a panel of 45 microRNAs that were present at elevated levels in the serum at the time of PPB diagnosis, with a significant majority noted be derived from the-3p strand (P1/40.013). In addition, we identified a subset of 10 serum microRNAs (namely miR-125a-3p, miR-125b-2-3p, miR-380-5p, miR-125b-1-3p, let-7f-2-3p, let-7a-3p, let-7b-3p, miR-708-3p, miR-138-1-3p and miR-532-3p) that were most abundant in the PPB case. Serum levels of two representative microRNAs, miR-125a-3p and miR-125b-2-3p, were not elevated in DICER1 germline-mutated relatives. In the PPB case, serum levels of miR-125a-3p and miR-125b-2-3p increased before chemotherapy, and then showed an early reduction following treatment. These microRNAs may offer future utility as serum biomarkers for screening patients with known germline DICER1 mutations for early detection of PPB, and for potential disease-monitoring in cases with confirmed PPB.

Original languageEnglish
Article numbere187
JournalOncogenesis
Volume3
Issue number2
DOIs
Publication statusPublished - 1 Jan 2014

Bibliographical note

Publisher Copyright:
© 2014 Macmillan Publishers Limited.

Keywords

  • DICER1
  • microRNA
  • pleuropulmonary blastoma
  • serum

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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