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

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.

Targeting mRNA processing as an anticancer strategy.

Discoveries in the past decade have highlighted the potential of mRNA as a therapeutic target for cancer. Specifically, RNA sequencing revealed that, in addition to gene mutations, alterations in mRNA can contribute to the initiation and progression of cancer. Indeed, precursor mRNA processing, which includes the removal of introns by splicing and the formation of 3' ends by cleavage and polyadenylation, is frequently altered in tumours. These alterations result in numerous cancer-specific mRNAs that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumour-suppressor genes. Abnormally spliced and polyadenylated mRNAs are also associated with resistance to cancer treatment and, unexpectedly, certain cancers are highly sensitive to the pharmacological inhibition of splicing. This Review summarizes recent progress in our understanding of how splicing and polyadenylation are altered in cancer and highlights how this knowledge has been translated for drug discovery, resulting in the production of small molecules and oligonucleotides that modulate the spliceosome and are in clinical trials for the treatment of cancer.