Methylation Suicide in Cancer (PQ10)

癌症中的甲基化自杀 (PQ10)

• 批准号: 8384250
• 负责人: TIMOTHY H BESTOR
• 金额: $ 33.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384250
• 关键词: Apoptosis; Base Sequence; Biological Markers; Breast Carcinoma; Cancer cell line; Cell Line; Cells; Characteristics; Copy Number Polymorphism; CpG Islands; DNA; DNA Methylation; Data; Detection; Diagnosis; Disease; Early Diagnosis; Etiology; Fatty acid glycerol esters; Gene Expression; Genome; Genomics; Growth; Human; Human Mammary Carcinoma; Hybrid Cells; Hybrids; Immune response; Incidence; Investigation; Literature; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mammary gland; Methods; Methylation; Molecular Profiling; Mus; NOD/SCID mouse; Nature; Noise; Pathway interactions; Pattern; Process; Publishing; Research; Role; Severities; Specific qualifier value; Suicide; Supporting Cell; System; Technology; Testing; Therapeutic; Time; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Xenograft procedure; base; cancer cell; cancer genome; carcinogenesis; demethylation; genome-wide; insight; killings; malignant breast neoplasm; neoplastic cell; novel strategies; promoter; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): It has long been believed that abnormal DNA methylation turns of tumor suppressor genes during carcinogenesis, but no biomarker or therapeutic approach has resulted. We find that abnormal de novo methylation at tumor suppressor genes is very rare, and that the dominant abnormality is a loss of DNA methylation across the genome. While demethylation in cancer has been regarded as a contributor to tumor progression, the data shown here indicate instead that is more likely to be a manifestation of a methylation-based antitumor system that induces apoptosis of tumor cells and elicits an antitumor immune response. Further investigation of genome demethylation in cancer may produce new approaches to diagnosis and treatment. Demethylation occurs early in tumorigenesis, and it may be possible to devise treatments that will augment the methylation suicide pathway so as to reduce the incidence or severity of malignant disease. The stability and sensitivity of detection of DNA biomarkers as compared to other biomolecules suggests that the identification of DNA methylation biomarkers through whole-genome methylation profiling could be effective in enhancing early diagnosis. PUBLIC HEALTH RELEVANCE: Our preliminary data and re-examination of published data have led us to re-evaluate the role of abnormalities of genomic methylation patterns in breast cancer. We conclude that the methylation abnormalities that occur curing carcinogenesis are likely to be a manifestation of a protective system that kills incipient cancer cells.

描述（由申请人提供）：长期以来，人们一直认为肿瘤抑制基因在癌变过程中DNA甲基化异常，但没有生物标志物或治疗方法。我们发现肿瘤抑制基因的异常从头甲基化是非常罕见的，主要的异常是整个基因组中DNA甲基化的缺失。虽然癌症中的去甲基化一直被认为是肿瘤进展的一个因素，但这里显示的数据表明，这更可能是一种基于甲基化的抗肿瘤系统的表现，该系统诱导肿瘤细胞凋亡并引发抗肿瘤免疫反应。进一步研究基因组去甲基化在癌症中的作用可能会产生新的诊断和治疗方法。去甲基化发生在肿瘤发生的早期，有可能设计出增加甲基化自杀途径的治疗方法，从而降低恶性疾病的发病率或严重程度。与其他生物分子相比，DNA生物标记物检测的稳定性和敏感性表明，通过全基因组甲基化谱鉴定DNA甲基化生物标记物可以有效地提高早期诊断。