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HIST1H2BB and MAGI2 Methylation and Somatic Mutations As Precision Medicine Biomarkers for Diagnosis and Prognosis of High-Grade Serous Ovarian Cancer Blanca L

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HIST1H2BB and MAGI2 Methylation and Somatic Mutations As Precision Medicine Biomarkers for Diagnosis and Prognosis of High-Grade Serous Ovarian Cancer Blanca L Published OnlineFirst June 24, 2020; DOI: 10.1158/1940-6207.CAPR-19-0412 CANCER PREVENTION RESEARCH | RESEARCH ARTICLE HIST1H2BB and MAGI2 Methylation and Somatic Mutations as Precision Medicine Biomarkers for Diagnosis and Prognosis of High-grade Serous Ovarian Cancer Blanca L. Valle1, Sebastian Rodriguez-Torres2,3, Elisabetta Kuhn4,5, Teresa Díaz-Montes6, Edgardo Parrilla-Castellar7, Fahcina P. Lawson1, Oluwasina Folawiyo1, Carmen Ili-Gangas8, Priscilla Brebi-Mieville8, James R. Eshleman9, James Herman3, Ie-Ming Shih4, David Sidransky1, and Rafael Guerrero-Preston1,10,11 ABSTRACT ◥ Molecular alterations that contribute to long-term (LT) (n ¼ 35). Immunoblot and clonogenic assays after pharma- and short-term (ST) survival in ovarian high-grade serous cologic unmasking show that HIST1H2BB and MAGI2 carcinoma (HGSC) may be used as precision medicine promoter methylation downregulates mRNA expression biomarkers. DNA promoter methylation is an early event levels in ovarian cancer cells. We then used qMSP in paired in tumorigenesis, which can be detected in blood and urine, tissue, ascites, plasma/serum, vaginal swabs, and urine from making it a feasible companion biomarker to somatic muta- a third cohort of patients with HGSC cancer (n ¼ 85) to test tions for early detection and targeted treatment workflows. the clinical potential of HIST1H2BB and MAGI2 in precision We compared the methylation profile in 12 HGSC tissue medicine workflows. We also performed next-generation samples to 30 fallopian tube epithelium samples, using the exome sequencing of 50 frequently mutated in human cancer Infinium Human Methylation 450K Array. We also used genes, using the Ion AmpliSeqCancer Hotspot Panel, to 450K methylation arrays to compare methylation among show that the somatic mutation profile found in tissue and HGSCs long-term survivors (more than 5 years) and short- plasma can be quantified in paired urine samples from term survivors (less than 3 years). We verified the array patients with HGSC. Our results suggest that HIST1H2BB results using bisulfite sequencing and methylation-specific and MAGI2 have growth-suppressing roles and can be used PCR (qMSP). in another cohort of HGSC patient samples as HGSC precision medicine biomarkers. Introduction 1Otolaryngology Department, Head and Neck Cancer Research Division, The Johns Hopkins University, School of Medicine, Baltimore, Maryland. 2Depart- Ovarian cancer is the fifth cause of cancer-related deaths ment of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, among women, and the most lethal gynecologic malignancy (1). Massachusetts. 3Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania. 4Division of Pathology, Fondazione IRCCS Clinical and molecular factors that contribute to long-term Ca’ Granda, Ospedale Maggiore Policlinico; Department of Biomedical, Surgical, (LT) and short-term (ST) survival in ovarian high-grade serous and Dental Sciences, University of Milan, Italy. 5Departments of Pathology, cancer (HGSC) are lacking and only a few molecular alterations Gynecology and Obstetrics, The Johns Hopkins University, School of Medicine, of response to therapy have been identified. Somatic mutations Baltimore, Maryland. 6The Lya Segall Ovarian Cancer Institute, Mercy Medical Center, Baltimore, Maryland. 7Department of Pathology, University of Washing- are rare in HGSC (2), BRCA1/2 germline mutations, and ton, Seattle, Washington. 8Laboratory Integrative Biology (LIBi), Center for homologous repair deficiency in HGSC are among the few Excellence in Translational Medicine-Scientific and Technological Bioresources validated molecular predictors of response to platinum therapy Nucleus (CEMT-BIOREN), Universidad de La Frontera, Temuco, Chile. 9Depart- – ment of Pathology, Johns Hopkins University, School of Medicine, Baltimore, and PARP inhibitors (3 6). Maryland. 10University of Puerto Rico School of Medicine, Department of DNA promoter methylation is an early event in tumorigen- Obstetrics and Gynecology, San Juan, Puerto Rico. 11LifeGene Biomarks Inc., esis, and can be detected in blood and other body fluids, making San Juan, Puerto Rico. it a feasible biomarker for early detection of tumors.(7–9) In Note: Supplementary data for this article are available at Cancer Prevention addition, DNA methylation has potential as a prognostic Research Online (http://cancerprevres.aacrjournals.org/). biomarker. For instance, the FDA has recently approved Corresponding Author: Rafael Guerrero-Preston, University of Puerto Rico EpiColon, a blood-based test for diagnosis of colorectal cancer School of Medicine, San Juan, PR 00927. E-mail: [email protected] based on methylation of septin 9 (10). Detection of promoter Cancer Prev Res 2020;13:1–12 methylation in tissues and biofluids represents a potential doi: 10.1158/1940-6207.CAPR-19-0412 biomarker strategy for ovarian cancer diagnosis and therapeu- Ó2020 American Association for Cancer Research. tic management within precision medicine workflows. AACRJournals.org | OF1 Downloaded from cancerpreventionresearch.aacrjournals.org on September 27, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst June 24, 2020; DOI: 10.1158/1940-6207.CAPR-19-0412 Valle et al. Until recently, epithelial ovarian cancers were thought to Library kit 2.0 according to the manufacturer’s instructions arise from the ovarian surface epithelial cells (11). However, (Life Technologies). Included in this panel were primers for 207 recent studies suggest that many of HGSCs arise from lesions in amplicons covering 2,800 Catalog of Somatic Mutations in the fallopian tubes (12–17). In this study, we sought to identify Cancer of 50 genes with known cancer associations: ABL1, genes differentially methylated between fallopian tube tissue AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, and HGSC and test whether ovarian cancer associated DNA CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, methylation and somatic mutations measured in tissue can be FGFR2, FGFR3, FLT3, GNA11, GNAS, GNAQ, HNF1A, HRAS, reproducibly measured in urine samples. IDH1, JAK2, JAK3, IDH2, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, Materials and Methods PTPN11, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53 and VHL. (COSMIC, http://cancer.sanger.ac.uk/cancer Patient samples genome/projects/cosmic). Ten nanograms DNA from the tumor The study population consists of samples from three patient samples was used as the template to prepare the library. cohorts (n ¼ 77) and publicly available data from 1,742 Amplified libraries were quantified using the Qubit 2.0 Fluo- patients: a retrospective cohort of HGSC formalin fixed and rometer and the High Sensitivity Qubit Assay Kit (Life Tech- paraffin embedded (FFPE) samples selected from Johns Hop- nologies). Amplified libraries were assessed for quality (size and kins Pathology Department tumor bank (n ¼ 12); a cohort of concentration) using the Agilent 2100 Bioanalyzer Instrument women who were seen in the Ohio State University School of (Agilent Technologies) following the Bioanalyzer standard Medicine Obstetrics and Gynecology Department (n ¼ 30); a protocol. The AmpliSeq libraries were clonally amplified on cohort of patients with HGSC who were seen in Mercy Medical to Ion Sphere Particles (ISP) using emulsion PCR following Center in Baltimore, MD (n ¼ 35); and data from the Cancer standard Ion Torrent protocols. ISP preparation was per- Genome Atlas Project (TCGA). The inclusion criterion was to formed using the automated Ion Torrent OneTouch2 system have a clinical diagnosis of HGCS (ICD9-CM code 183), all following the manufacturer’s protocol (MAN0007220 Revision determined by pathologists at two different institutions Hop- 4.0). The Qubit Fluorometer was used to assess ISP quality after kins and Mercy Medical Center. The Institutional Review ISP preparation but before ISP enrichment. Up to eight speci- Boards of Ohio State School of Medicine, Mercy Medical mens were barcoded with Ion Xpress Barcode Adapters (Life Center and Johns Hopkins School of Medicine (NA_00020633) Technologies), pooled, and run on a single Ion 318 chip. This approved the research protocols. Informed written consent was includes multiple patient samples and one control, which we obtained from all patients included in the study. rotate among water, normal, and a mix of positive control cell lines. Cancer genome atlas project data TCGA data was downloaded and analyzed for DNA meth- Methylation 450K arrays ylation alterations using the minfi package. Somatic mutation We sought to determine genes differentially methylated in and expression data were downloaded from the cBioPortal ovarian cancer as compared with fallopian tube epithelium, (http://www.cbioportal.org/). therefore we compared the methylation status in 12 HGSC FFPE tissue samples to 30 fallopian tube epithelium samples DNA extraction using the genome-wide Infinium HumanMethylation 450K DNA was extracted from frozen normal fallopian tube Array. The HumanMethylation450K DNA BeadChip assay epithelium, FFPE HGSC tissue samples, as well as from normal was used to perform unbiased genome-wide DNA methylation and ovarian cancer cell lines. Biofluids DNA was extracted as analysis. Bisulfite modification of genomic DNA (2 mg) was described previously (11, 18). The protocol for trans-renal performed with EpiTect Bisulfite Kit (Qiagen) according to the DNA extraction reduces the possibility of contamination from manufacturer’s protocol. We hybridized bisulfite-converted
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