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Expression Profiling in Ovarian Cancer Reveals Coordinated Regulation of BRCA1/2 and Homologous Recombination Genes

Noélia Custódio1, Rosina Savisaar1, Célia Carvalho1

  • 1Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisboa, Portugal.

Biomedicines
|February 25, 2022
PubMed

Insights

Quantifying BRCA1/2 mRNA levels in ovarian tumors offers valuable insights beyond DNA tests. This approach can identify patients likely to benefit from poly(ADP-ribose) polymerase inhibitors (PARPi) therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) are effective for ovarian cancer patients with homologous recombination (HR) deficiency.
  • BRCA1/2 mutations are common indicators of HR deficiency, but current genetic tests have limitations.
  • Genetic tests may yield inconclusive results due to variants of unknown significance or fail to detect epigenetic modifications and deep intronic mutations affecting mRNA.

Purpose of the Study:

  • To investigate if quantifying BRCA1/2 messenger RNA (mRNA) levels in ovarian cancer provides additional clinical information compared to DNA tests.
  • To explore the correlation between BRCA1/2 mRNA expression and the expression of other HR genes.
  • To develop a clinically applicable method for measuring BRCA1/2 mRNA levels.

Main Methods:

  • RNA analysis using the nCounter assay from NanoString Technologies on 38 ovarian cancer specimens and 11 normal fallopian tube samples.
  • Validation using The Cancer Genome Atlas (TCGA) dataset of 299 ovarian cancer samples.
  • Development of a targeted droplet digital polymerase chain reaction (ddPCR) approach for FFPE samples.

Main Results:

  • BRCA1/2 mRNA expression exhibited significant variability among ovarian tumors.
  • Tumors with lower BRCA1/2 mRNA levels showed coordinated downregulation of 12 additional HR genes.
  • The developed ddPCR method is suitable for routine clinical analysis of BRCA1/2 mRNA in FFPE samples.

Conclusions:

  • Measuring BRCA1/2 mRNA levels can offer crucial predictive information for PARPi therapy in ovarian cancer.
  • This approach provides benefits when traditional BRCA1/2 DNA tests are negative or inconclusive.
  • Quantifying mRNA expression is a valuable adjunct to DNA testing for optimizing ovarian cancer treatment strategies.
Keywords:
BRCA1/2 mRNAddPCRhomologous recombinationnCounter assayovarian cancer

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