Abstract
Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The “BRCAness” status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver’s operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.The application of chemotherapy as the standard treatment for advanced-stage ovarian cancer has been associated with little progress in improving the long-term clinical outcomes [1]
This has led to more targeted therapeutic approaches in the management of ovarian cancer including the use of poly-ADP-ribose-polymerase inhibitors (PARPis)
We describe the overall clinical diagnostic yield as determined by sequence variant analysis and evaluate the improvements achieved by the incorporation of copy-number variation (CNV) and promoter DNA methylation evaluation of BRCA1/2
Summary
The application of chemotherapy as the standard treatment for advanced-stage ovarian cancer has been associated with little progress in improving the long-term clinical outcomes [1]. This has led to more targeted therapeutic approaches in the management of ovarian cancer including the use of poly-ADP-ribose-polymerase inhibitors (PARPis). Initial Phase-II clinical trials have shown a significantly longer progression-free survival in the PARPitreated patients as compared with those receiving placebo (8.4 vs 4.8 months), with a more pronounced effect in subjects that had germline or somatic BRCA1/2 mutations (11.2 vs 4.3 months) [3]. Randomized controlled trials (RCTs) have shown improved progression-free survival in BRCA1/2 mutation carriers when PARPis are
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
