Somatic Variants in DNA Damage Response Genes in Ovarian Cancer Patients Using Whole-exome Sequencing.

BACKGROUND/AIM: Several clinical trials have investigated homologous recombination deficiency and BRCA1/2 status to select ovarian cancer patients for treatment with poly(ADP-ribose) polymerase-inhibitors (PARPi), but less attention has been given to other DNA-damage response (DDR) pathways. Therefore, we investigated somatic single/multiple nucleotide variants and small insertions/deletions in exonic and splice-site regions of 356 DDR genes to examine whether genes other than BRCA1/2 are altered. MATERIALS AND METHODS: Whole-exome sequencing data from eight high-grade serous adenocarcinoma (HGSC) and four clear cell carcinoma (oCCC) patients were analyzed. RESULTS: Forty-two variants (pathogenic, likely pathogenic or variants of uncertain significance) in 28 genes from DDR pathways were identified. Seven out of nine TP53 variants were previously described in The Cancer Genome Atlas Ovarian Cancer; other variants were found in 23 out of 28 unique genes, whereas no variants were reported in FAAP24, GTF2H4, POLE4, RPA3, and XRCC4. CONCLUSION: As the identified variants were not only limited to well-known TP53, BRCA1/2, and HR-associated genes, our study might contribute to the better understanding of which DDR pathways potentially influence disease progression. Moreover, they may display a potential role as biomarkers to predict platinum-based chemotherapy or PARPi treatment response or disease progression, as differences in disrupted DDR pathways were observed between patients with long and short overall survival in HGSC and oCCC groups.

Identification of Stably Expressed Reference microRNAs in Epithelial Ovarian Cancer.

BACKGROUND/AIM: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression and have been associated with the development of various cancers, including epithelial ovarian cancer (EOC). Accurate quantification of miRNA levels is important for determining their role in tumorigenesis and as biomarkers. Currently, U6 is widely used as a normalization control when investigating miRNAs in EOC; however, its variable expression across cancers has been reported. As only a few studies have been published to date on the identification of endogenous miRNA controls in EOC, our aim was to identify stable miRNAs based on global microarray profiling of 197 EOC patients and verify their stability in external datasets. MATERIALS AND METHODS: We collected miRNA-microarray data from four datasets: the in-house "Pelvic Mass", and three public datasets with primary EOC patients: The Cancer Genome Atlas, GSE47841, and GSE73581. The expression stability of endogenous control candidates was evaluated by their coefficient of variation. RESULTS: All miRNA results in the used cohorts were produced by either Affymetrix or Agilent technologies, which show similar intra-platform patterns. Nonetheless, a clear difference in a cross-platform comparison was observed. We identified hsa-miR-92b-5p and hsa-miR-106b-3p as stable candidates shared between four datasets. Moreover, we investigated the stability performance of eight miRNAs that have been previously reported as stable endogenous controls in EOC and various performance was observed in four datasets. CONCLUSION: The selection of suitable endogenous miRNA normalization controls in EOC remains to be resolved, as variability in miRNA performance between platforms might have a crucial impact on the biological interpretation of data.