Methylated DNA markers discriminate ovarian cancer from benign tissue in BRCA carriers.

person Jessica Weng Mayo Clinic Alix School of Medicine, Rochester, MN info_outline Jessica Weng, Jamie Nadine Bakkum-Gamez, Seth Slettedahl, Douglas W. Mahoney, Xiaoming Cao, Patrick H. Foote, Kelli Burger, Calise K. Berger, Maria O'Connell, Jacquelyn R. Arndt, Karen A. Doering, Mark E. Sherman, William R. Taylor, Longwen Chen, Fergus Couch, John B. Kisiel, Jewel Samadder

Authors person Jessica Weng Mayo Clinic Alix School of Medicine, Rochester, MN info_outline Jessica Weng, Jamie Nadine Bakkum-Gamez, Seth Slettedahl, Douglas W. Mahoney, Xiaoming Cao, Patrick H. Foote, Kelli Burger, Calise K. Berger, Maria O'Connell, Jacquelyn R. Arndt, Karen A. Doering, Mark E. Sherman, William R. Taylor, Longwen Chen, Fergus Couch, John B. Kisiel, Jewel Samadder Organizations Mayo Clinic Alix School of Medicine, Rochester, MN, Mayo Clinic, Rochester, MN, Mayo Clinic, Jacksonville, FL, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, Mayo Clinic, Phoenix, AZ Abstract Disclosures Research Funding U.S. National Institutes of Health Gerstner award, Center for Individualized Medicine, Mayo Clinic Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2 ) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1 ) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin , by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA ) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA -OC) and 48 BOT ( BRCA -BOT); among non- BRCA , we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA -BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA -BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies. AUCs (95% confidence interval) for selected MDMs in discrimination of OC from BOT from BRCA1/2 carrier and sporadic patients. Sporadic BRCA1/2 p-value GDF6 0.99 (0.98-1) 0.99 (0.97-1) 0.9 IFFO1 0.94 (0.89-1) 0.95 (0.89-1) 1.0 NCOR2 0.87 (0.78-0.95) 0.94 (0.89-0.99) 0.1 PDRM14 0.88 (0.8-0.96) 0.94 (0.88-1) 0.2 MAX.chr1.147790358 0.97 (0.93-1) 0.92 (0.85-0.99) 0.2 MAX.chr6.10382190 0.90 (0.83-0.97) 0.91 (0.84-0.98 0.8 C2CD4D 0.96 (0.91-1) 0.90 (0.82-0.98) 0.2