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

基本信息

批准号：
8050151
负责人：
Darryl K Shibata
金额：
$ 17.09万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-03-31
项目状态：
已结题

项目摘要

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）：某些患者的化学疗法成功，但是很难预测哪些患者将受益。我们建议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包含罕见的先前抗性变体细胞通常被认为是导致复发的原因（Goldie-Coldman假设）。癌症最初可能是同质的，并且对化学疗法敏感，但是随着时间的流逝，癌症变成了多态性，并且更有可能获得抗性变体细胞。目前没有量化癌症多样性的方法，我们建议翻译成良好的人口遗传学方法来测量III期结肠直肠癌多样性。由于在人类癌症中体细胞突变相对较少，因此将测量中性CpG富基因座（“乘客甲基化”）更容易检测到的表观遗传DNA甲基化模式变化。通过对来自同一癌症不同部位的多个上皮样品取样，可以使用比较同源CpG位点上甲基化状态的成对距离来定量肿瘤多样性。更多样化的癌症应具有更多的异质乘客甲基化模式和更大的平均成对距离。由于人群遗传学家很少依赖单个基因来量化多样性，因此我们建议开发十个不同的乘客甲基化基因座。将在多个乘客基因座上测量50期III阶段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可能含有预先存在的抗性变异细胞，因此在化学疗法后鉴定出更有可能保持缓解的个别患者。公共卫生相关性：预先存在的抗性变异细胞被认为是化学疗法后复发的原因 - 更有多样化的肿瘤更有可能含有化学耐药性变异细胞。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。这种多样性生物标志物可以更好地预测哪些患者更有可能从化学疗法中受益。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.

DOI：
10.1126/science.1227670
发表时间：
2013-02-01
期刊：
SCIENCE
影响因子：
56.9
作者：
Kreso, Antonija;O'Brien, Catherine A.;van Galen, Peter;Gan, Olga I.;Notta, Faiyaz;Brown, Andrew M. K.;Ng, Karen;Ma, Jing;Wienholds, Erno;Dunant, Cyrille;Pollett, Aaron;Gallinger, Steven;McPherson, John;Mullighan, Charles G.;Shibata, Darryl;Dick, John E.
通讯作者：
Dick, John E.

Mutation and epigenetic molecular clocks in cancer.