Tumor Diversity As A Biomarker For Colorectal Cancer

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可能含有罕见的预先存在的耐药变异细胞，通常认为这是复发的原因（Goldie-Coldman假说）。癌症最初可能是同质的，对化疗敏感，但随着时间的推移变得多态，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，我们建议将成熟的群体遗传学方法转化为测量III期结直肠癌多样性的方法。由于体细胞突变在人类癌症中相对罕见，因此将测量在中性CpG富集基因座处更容易检测的表观遗传DNA甲基化模式变异（“乘客甲基化”）。通过从同一癌症的不同部分取样多个表观等位基因，可以使用比较同源CpG位点处的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于一个单一的基因来量化多样性，我们建议开发一套10个不同的乘客甲基化位点。将在多个乘客基因座测量50例III期结直肠癌的平均多样性，以回顾性地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可能含有预先存在的耐药变异细胞，从而确定个体患者在化疗后更有可能保持缓解。 公共卫生相关性：先前存在的耐药变异细胞被认为是化疗后复发的原因-更多样化的肿瘤更可能含有耐药变异细胞。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预后较差的生物标志物。这种多样性生物标志物可以更好地预测哪些患者更有可能从化疗中获益。

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.