DNA methylation landscapes of matched primary and recurrent high grade serous ovarian cancers are preserved throughout disease progression and chemoresistance
Silva Tiago C. 1Karlan Beth Y. 2Berg Yonatan 3Govindavari John-Paul B. 4Gull Nicole 5Jones Michelle R. 5Peng Pei-Chen 5Coetzee Simon G. 5Reyes Alberto Luiz P. 5Davis Brian D. 6Li Andrew J. 7Chen Stephanie 6Gayther Simon A. 6Lawrenson Kate 8Lester Jenny 2Rutgers Joanna K.L. 4Cass Ilana 9Plummer Jasmine T. 6Rimel Bobbie J. 7Walsh Christine 7Berman Benjamin P.10
作者信息
- 1. Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miller School of Medicine
- 2. Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center||Department of Obstetrics and Gynecology, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA
- 3. Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School
- 4. Department of Pathology, Cedars-Sinai Medical Center
- 5. Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center
- 6. Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center||Applied Genomics, Computation and Translational Core, Cedars Sinai Medical Center
- 7. Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center||Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center
- 8. Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center||Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center||Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center
- 9. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center
- 10. Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center||Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School
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Abstract
ABSTRACT
Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing (WGBS) and whole transcriptome sequencing (RNA-seq) to establish methylation and gene expression signatures in 62 primary and recurrent tumors from 28 patients diagnosed with stage III/IV HGSOC. Eleven of these patients carried pathogenic germline BRCA1/BRCA2 mutations. Genome-wide methylation and transcriptomic features identified in primary tumors were largely preserved in matched recurrent tumors from the same patient (P-value = 7.16 × 10?7 and 1.41 × 10?3 in BRCA1/2 and non-BRCA1/2 cases respectively). Tumors from BRCA1/2 carriers displayed high levels of heterogeneity, with significantly more shared methylation changes identified between primary and recurrent tumors from non-BRCA1/2 patients, which may be related to the poorer survival we observe in HGSOCs from non-BRCA1/2 carriers (P-value = 0.0056). Partially methylated domains (PMDs) dominated the epigenetic variation across all tumors, and were more hypomethylated in BRCA1/2 than non-BRCA1/2 cases. Differential gene expression analysis identified upregulation of genes from immune pathways including antigen processing and presentation in tumors from BRCA1/2 carriers, implicating increased immune response in the improved survival observed in these patients. In summary, this study shows a previously unreported conservation of methylation and gene expression in recurrent HGSOCs. These data have implications for the possible effectiveness of epigenetic based therapies to treat both primary and recurrent ovarian cancers.引用本文复制引用
Silva Tiago C.,Karlan Beth Y.,Berg Yonatan,Govindavari John-Paul B.,Gull Nicole,Jones Michelle R.,Peng Pei-Chen,Coetzee Simon G.,Reyes Alberto Luiz P.,Davis Brian D.,Li Andrew J.,Chen Stephanie,Gayther Simon A.,Lawrenson Kate,Lester Jenny,Rutgers Joanna K.L.,Cass Ilana,Plummer Jasmine T.,Rimel Bobbie J.,Walsh Christine,Berman Benjamin P..DNA methylation landscapes of matched primary and recurrent high grade serous ovarian cancers are preserved throughout disease progression and chemoresistance[EB/OL].(2025-03-28)[2026-05-08].https://www.biorxiv.org/content/10.1101/2020.08.25.267161.学科分类
基础医学/肿瘤学/分子生物学
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