Molecular alterations that contribute to long-term (LT) and short-term (ST) survival in ovarian high-grade serous carcinoma (HGSC) may be used as precision medicine biomarkers. DNA promoter methylation is an early event in tumorigenesis, which can be detected in blood and urine, making it a feasible companion biomarker to somatic mutations for early detection and targeted treatment workflows. We compared the methylation profile in 12 HGSC tissue samples to 30 fallopian tube epithelium samples, using the Infinium Human Methylation 450K Array. We also used 450K methylation arrays to compare methylation among HGSCs long-term survivors (more than 5 years) and short-term survivors (less than 3 years). We verified the array results using bisulfite sequencing and methylation-specific PCR (qMSP). in another cohort of HGSC patient samples (n = 35). Immunoblot and clonogenic assays after pharmacologic unmasking show that HIST1H2BB and MAGI2 promoter methylation downregulates mRNA expression levels in ovarian cancer cells. We then used qMSP in paired tissue, ascites, plasma/serum, vaginal swabs, and urine from a third cohort of patients with HGSC cancer (n = 85) to test the clinical potential of HIST1H2BB and MAGI2 in precision medicine workflows. We also performed next-generation exome sequencing of 50 frequently mutated in human cancer genes, using the Ion AmpliSeqCancer Hotspot Panel, to show that the somatic mutation profile found in tissue and plasma can be quantified in paired urine samples from patients with HGSC. Our results suggest that HIST1H2BB and MAGI2 have growth-suppressing roles and can be used as HGSC precision medicine biomarkers.

中文翻译：

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HIST1H2BB和MAGI2甲基化和体细胞突变作为高级别浆液性卵巢癌诊断和预后的精准医学生物标志物

有助于卵巢高级别浆液性癌 (HGSC) 长期 (LT) 和短期 (ST) 存活的分子改变可用作精准医学生物标志物。DNA 启动子甲基化是肿瘤发生的早期事件，可以在血液和尿液中检测到，使其成为体细胞突变的可行伴随生物标志物，用于早期检测和靶向治疗工作流程。我们使用 Infinium Human Methylation 450K Array 比较了 12 个 HGSC 组织样本与 30 个输卵管上皮样本中的甲基化特征。我们还使用 450K 甲基化阵列来比较 HGSCs 长期存活者（超过 5 年）和短期存活者（不到 3 年）的甲基化。我们使用亚硫酸氢盐测序和甲基化特异性 PCR (qMSP) 验证了阵列结果。在另一组 HGSC 患者样本中（n = 35）。药理学揭示后的免疫印迹和克隆测定表明 HIST1H2BB 和 MAGI2 启动子甲基化下调卵巢癌细胞中的 mRNA 表达水平。然后，我们在来自第三组 HGSC 癌症患者（n = 85）的配对组织、腹水、血浆/血清、阴道拭子和尿液中使用 qMSP，以测试 HIST1H2BB 和 MAGI2 在精准医学工作流程中的临床潜力。我们还使用 Ion AmpliSeqCancer Hotspot Panel 对人类癌症基因中的 50 个经常突变的基因进行了下一代外显子组测序，以表明可以在 HGSC 患者的配对尿液样本中量化在组织和血浆中发现的体细胞突变谱。我们的结果表明 HIST1H2BB 和 MAGI2 具有生长抑制作用，可用作 HGSC 精准医学生物标志物。