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Original article
Small RNA sequencing reveals a comprehensive miRNA signature of BRCA1-associated high-grade serous ovarian cancer
  1. Jan Brouwer1,
  2. Joost Kluiver2,
  3. Rodrigo C de Almeida3,4,
  4. Rutger Modderman3,
  5. Miente Martijn Terpstra3,
  6. Klaas Kok3,
  7. Sebo Withoff3,
  8. Harry Hollema2,
  9. Welmoed Reitsma1,
  10. Geertruida H de Bock5,
  11. Marian J E Mourits1,
  12. Anke van den Berg2
  1. 1Department of Gynecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  2. 2Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  4. 4Departamento de Genética, Universidade Federal do Paraná, Curitiba, PR, Brazil
  5. 5Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Professor Anke van den Berg, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9700 RB, The Netherlands; a.van.den.berg01{at}umcg.nl

Abstract

Aims BRCA1 mutation carriers are at increased risk of developing high-grade serous ovarian cancer (HGSOC), a malignancy that originates from fallopian tube epithelium. We aimed to identify differentially expressed known and novel miRNAs in BRCA1-associated HGSOC.

Methods Small RNA sequencing was performed on eight normal tubal and five HGSOC samples of BRCA1 carriers. Differential expression of a subset of known and novel miRNAs was validated by qRT-PCR on the samples used for small RNA sequencing and a second sample cohort comprising normal and HGSOC tissue of matched BRCA1 and non-BRCA carriers. Data from The Cancer Genome Atlas were used to determine the clinical relevance of the validated differentially expressed miRNAs.

Results 59 known and 20 novel miRNAs showed a significant >fourfold expression difference between normal tubal tissue and HGSOC. qRT-PCR validation confirmed a significant difference in expression levels for 10 out of 11 known miRNAs. Upregulation of two novel miRNAs could not be confirmed. Interestingly, for seven miRNAs a significant increase in expression was observed when comparing normal tubal tissue of postmenopausal women with premenopausal women. Expression levels of miR-145-5p significantly increased with International Federation of Gynecology and Obstetrics stage, while the expression levels of the other nine validated miRNAs were not associated with clinical characteristics.

Conclusions We report a comprehensive expression signature including both known and novel miRNAs of BRCA1-associated HGSOC. Comparison with previous profiling studies showed a good overlap and a large number of miRNAs not reported to be differentially expressed in HGSOC before underscoring the importance of this study.

  • OVARIAN TUMOUR
  • MOLECULAR ONCOLOGY
  • FALLOPIAN TUBE

https://doi.org/10.1136/jclinpath-2016-203679

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    Footnotes

    • Handling editor Runjan Chetty

    • Contributors Study design: all authors. Data acquisition: JB and RM. Data analysis and interpretation: JB, JK, GHdB, MJEM and AvdB. Manuscript writing: JB, MJEM and AvdB. All authors named in the title page have contributed to, read and approved the final version of the manuscript.

    • Funding This project was financially supported by the Graduate School of Medical Sciences, University Medical Center Groningen.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement When interested, researchers can contact the corresponding author for possible transfer of raw data.