Tumor Diversity As A Biomarker For Colorectal Cancer

肿瘤多样性作为结直肠癌的生物标志物

• 批准号: 7874806
• 负责人: Darryl K Shibata
• 金额: $ 21.17万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874806
• 关键词: Biological Markers; Cells; Clinical; Colorectal Cancer; DNA Methylation; Disease remission; Epigenetic Process; Genes; Human; Individual; Malignant Neoplasms; Measures; Methods; Methylation; Outcome; Patients; Pattern; Population; Population Genetics; Recurrence; Relapse; Resistance; Sampling; Site; Somatic Mutation; Staging; Testing; Therapeutic; Time; Translating; Variant; cancer therapy; chemotherapy; public health relevance; response; tumor

DESCRIPTION (provided by applicant): Chemotherapy is successful in some patients, but it has been difficult to predict which individual patients will benefit. We propose that tumor diversity levels can predict therapeutic responses because more diverse tumors more likely contain the rare pre-existing resistant variant cells commonly thought to be responsible for recurrence (Goldie-Coldman hypothesis). A cancer may be initially homogeneous and sensitive to chemotherapy, but with time becomes polymorphic and more likely to acquire resistant variant cells. There are currently no methods that quantify cancer diversity, and we propose to translate well-established population genetics approaches to measure Stage III colorectal cancer diversity. Because somatic mutations are relatively rare in human cancers, more easily detected epigenetic DNA methylation pattern variation at neutral CpG rich loci ("passenger methylation") will be measured. By sampling multiple epialleles from different parts of the same cancer, tumor diversity can be quantified using pairwise distances that compare methylation status at homologous CpG sites. More diverse cancers should have more heterogeneous passenger methylation patterns and greater average pairwise distances. Because population geneticists seldom rely on a single gene to quantify diversity, we propose to develop a set of ten different passenger methylation loci. The average diversity of 50 Stage III colorectal cancers will be measured at multiple passenger loci to retrospectively test whether higher diversity levels correlate with recurrence. Diversity levels may predict which tumors more likely contain pre-existing resistant variant cells and therefore identify individual patients more likely to remain in remission after chemotherapy. PUBLIC HEALTH RELEVANCE: Pre-existing resistant variant cells are thought to be responsible for relapse after chemotherapy - more diverse tumors are more likely to contain chemoresistant variant cells. We propose to develop a method to quantify tumor diversity to test whether higher diversity is a biomarker for poorer outcomes. Such a diversity biomarker may better predict which patients would more likely benefit from chemotherapy.

描述（由申请人提供）：化疗对某些患者是成功的，但很难预测哪些患者会受益。我们认为肿瘤多样性水平可以预测治疗反应，因为更多样化的肿瘤更有可能含有罕见的预先存在的耐药变异细胞，这些细胞通常被认为是导致复发的原因（戈尔迪-科德曼假说）。癌症最初可能是同质的并且对化疗敏感，但随着时间的推移变得多态性并且更有可能获得耐药变异细胞。目前还没有量化癌症多样性的方法，我们建议转化成熟的群体遗传学方法来测量 III 期结直肠癌的多样性。由于体细胞突变在人类癌症中相对罕见，因此将测量中性 CpG 丰富位点（“乘客甲基化”）更容易检测到的表观遗传 DNA 甲基化模式变异。通过对同一癌症不同部位的多个表观等位基因进行采样，可以使用比较同源 CpG 位点甲基化状态的成对距离来量化肿瘤多样性。更多样化的癌症应该具有更异质的乘客甲基化模式和更大的平均成对距离。由于群体遗传学家很少依赖单个基因来量化多样性，因此我们建议开发一组十个不同的乘客甲基化位点。将在多个乘客位点测量 50 个 III 期结直肠癌的平均多样性，以回顾性测试较高的多样性水平是否与复发相关。多样性水平可以预测哪些肿瘤更有可能含有预先存在的耐药变异细胞，从而识别出更有可能在化疗后保持缓解状态的个体患者。 公共健康相关性：先前存在的耐药变异细胞被认为是化疗后复发的原因 - 肿瘤越多样化，就越可能含有化疗耐药变异细胞。我们建议开发一种量化肿瘤多样性的方法，以测试较高的多样性是否是较差结果的生物标志物。这种多样性的生物标志物可以更好地预测哪些患者更有可能从化疗中受益。