Abstract
Predictive biomarkers are crucial in clarifying the best strategy to use poly(ADP-ribose) polymerase inhibitors (PARPi) for the greatest benefit to ovarian cancer patients. PARPi are specifically lethal to cancer cells that cannot repair DNA damage by homologous recombination (HR), and HR deficiency is frequently associated with BRCA1/2 mutations. Genetic tests for BRCA1/2 mutations are currently used in the clinic, but results can be inconclusive due to the high prevalence of rare DNA sequence variants of unknown significance. Most tests also fail to detect epigenetic modifications and mutations located deep within introns that may alter the mRNA. The aim of this study was to investigate whether quantitation of BRCA1/2 mRNAs in ovarian cancer can provide information beyond the DNA tests. Using the nCounter assay from NanoString Technologies, we analyzed RNA isolated from 38 ovarian cancer specimens and 11 normal fallopian tube samples. We found that BRCA1/2 expression was highly variable among tumors. We further observed that tumors with lower levels of BRCA1/2 mRNA showed downregulated expression of 12 additional HR genes. Analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed the coordinated expression of BRCA1/2 and HR genes. To facilitate the routine analysis of BRCA1/2 mRNA in the clinical setting, we developed a targeted droplet digital PCR approach that can be used with FFPE samples. In conclusion, this study underscores the potential clinical benefit of measuring mRNA levels in tumors when BRCA1/2 DNA tests are negative or inconclusive.
Highlights
Ovarian cancer is the deadliest form of gynecological cancer [1,2]
We used the nCounter assay from NanoString Technologies because this is considered an ideal method for expression profiling in formalin-fixed and paraffin-embedded (FFPE) tissues
We measured the levels of BRCA1 and BRCA2 mRNA in ovarian cancers and normal fallopian tubes, the organ from which most ovarian cancers originate [25,26]
Summary
The average lifetime risk of developing ovarian cancer is 1.3%, the equivalent of 1 in 78 women [1]. Ovarian cancer accounts for 2.5% of all malignancies in women, it is responsible for 5%. Of female cancer deaths [2]. This high fatality rate is usually attributed to frequent late diagnosis, limited therapeutic options, and a lack of effective biomarkers for predicting treatment response [3]. The standard treatment for newly diagnosed ovarian cancer is cytoreductive surgery followed by platinum-based chemotherapy [4]. Approximately 70% of patients have a relapse within the subsequent 3 years [3]. Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment
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