Methylated DNA markers for plasma detection of ovarian cancer: Discovery, validation, and clinical feasibility.

Autor: Marinelli LM; Department of Pathology and Area Laboratory Services, San Antonio Military Medical Center, San Antonio, TX, United States of America., Kisiel JB; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Slettedahl SW; Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America., Mahoney DW; Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America., Lemens MA; Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America., Shridhar V; Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America., Taylor WR; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Staub JK; Department of Laboratory Medicine and Pathology, Experimental Pathology, Mayo Clinic, Rochester, MN, United States of America., Cao X; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Foote PH; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Burger KN; Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America., Berger CK; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., O'Connell MC; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Doering KA; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States of America., Giakoumopoulos M; Exact Sciences, Madison, WI, United States of America., Berg H; Exact Sciences, Madison, WI, United States of America., Volkmann C; Exact Sciences, Madison, WI, United States of America., Solsrud A; Exact Sciences, Madison, WI, United States of America., Allawi HT; Exact Sciences, Madison, WI, United States of America., Kaiser M; Exact Sciences, Madison, WI, United States of America., Vaccaro AM; Exact Sciences, Madison, WI, United States of America., Albright Crawford C; Exact Sciences, Madison, WI, United States of America., Moehlenkamp C; Exact Sciences, Madison, WI, United States of America., Shea G; Exact Sciences, Madison, WI, United States of America., Deist MS; Exact Sciences, Madison, WI, United States of America., Schoolmeester JK; Department of Laboratory Medicine and Pathology, Anatomic Pathology, Mayo Clinic, Rochester, MN, United States of America., Kerr SE; Hospital Pathology Associates, Minneapolis, MN, United States of America., Sherman ME; Quantitative Health Sciences, Mayo Clinic, Jacksonville, Florida, United States of America., Bakkum-Gamez JN; Obstetrics and Gynecology, Division of Gynecologic Oncology Surgery, Mayo Clinic, Rochester, MN, United States of America. Electronic address: bakkum.jamie@mayo.edu.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2022 Jun; Vol. 165 (3), pp. 568-576. Date of Electronic Publication: 2022 Mar 31.
DOI: 10.1016/j.ygyno.2022.03.018
Abstrakt: Objective: Aberrant DNA methylation is an early event in carcinogenesis which could be leveraged to detect ovarian cancer (OC) in plasma.
Methods: DNA from frozen OC tissues, benign fallopian tube epithelium (FTE), and buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify OC MDMs. Candidate MDM selection was based on receiver operating characteristic (ROC) discrimination, methylation fold change, and low background methylation among controls. Blinded biological validation was performed using methylated specific PCR on DNA extracted from independent OC and FTE FFPE tissues. MDMs were tested using Target Enrichment Long-probe Quantitative Amplified Signal (TELQAS) assays in pre-treatment plasma from women newly diagnosed with OC and population-sampled healthy women. A random forest modeling analysis was performed to generate predictive probability of disease; results were 500-fold in silico cross-validated.
Results: Thirty-three MDMs showed marked methylation fold changes (10 to >1000) across all OC subtypes vs FTE. Eleven MDMs (GPRIN1, CDO1, SRC, SIM2, AGRN, FAIM2, CELF2, RIPPLY3, GYPC, CAPN2, BCAT1) were tested on plasma from 91 women with OC (73 (80%) high-grade serous (HGS)) and 91 without OC; the cross-validated 11-MDM panel highly discriminated OC from controls (96% (95% CI, 89-99%) specificity; 79% (69-87%) sensitivity, and AUC 0.91 (0.86-0.96)). Among the 5 stage I/II HGS OCs included, all were correctly identified.
Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation yielded candidate MDMs for OC that performed with high sensitivity and specificity in plasma. Larger plasma-based OC MDM studies, including testing of pre-diagnostic specimens, are warranted.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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