title: Tumor hypomethylation at 6p21.3 associates with longer time to recurrence of high-grade serous epithelial ovarian cancer.
abstract: To reveal biologic mechanisms underlying clinical outcome of high-grade serous (HGS) epithelial ovarian carcinomas (EOC), we evaluated the association between tumor epigenetic changes and time to recurrence (TTR). We assessed methylation at approximately 450,000 genome-wide CpGs in tumors of 337 Mayo Clinic (Rochester, MN) patients. Semi-supervised clustering of discovery (n=168) and validation (n=169) sets was used to determine clinically relevant methylation classes. Clustering identified two methylation classes based on 60 informative CpGs, which differed in TTR in the validation set [R vs. L class, P=2.9×10(-3), HR=0.52; 95% confidence interval (CI), 0.34-0.80]. Follow-up analyses considered genome-wide tumor mRNA expression (n=104) and CD8 T-cell infiltration (n=89) in patient subsets. Hypomethylation of CpGs located in 6p21.3 in the R class associated with cis upregulation of genes enriched in immune response processes (TAP1, PSMB8, PSMB9, HLA-DQB1, HLA-DQB2, HLA-DMA, and HLA-DOA), increased CD8 T-cell tumor infiltration (P=7.6×10(-5)), and trans-regulation of genes in immune-related pathways (P=1.6×10(-32)). This is the most comprehensive assessment of clinical outcomes with regard to epithelial ovarian carcinoma tumor methylation to date. Collectively, these results suggest that an epigenetically mediated immune response is a predictor of recurrence and, possibly, treatment response for HGS EOC.
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Mine S
authors.initials: MS
authors.lastname: Cicek
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Bridget
authors.initials: B
authors.lastname: Charbonneau
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Kimberly R
authors.initials: KR
authors.lastname: Kalli
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Sebastian M
authors.initials: SM
authors.lastname: Armasu
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Larson
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Boris
authors.initials: B
authors.lastname: Winterhoff
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chien
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Block
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Hartmann
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Visscher
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida.
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.affiliation: Authors' Affiliations: Departments of Health Sciences Research, Medical Oncology, Obstetrics and Gynecology, and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Department of Research, Illumina, San Diego, California; Departments of Cancer Biology and Biostatistics, University of Kansas Medical Center, Kansas City, Kansas; and Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida egoode@mayo.edu.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Goode
mesh_terms: D000328:Adult; D000077216:Carcinoma, Ovarian Epithelial; D002896:Chromosomes, Human, Pair 6; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000276:immunology; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology; D015854:Up-Regulation; D055815:Young Adult
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