权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Genetic Modifiers of Intitiation and Progression of Mammary Cancer

乳腺癌发生和进展的基因修饰因素

基本信息

批准号：
7966645
负责人：
KENT William HUNTER
金额：
$ 171.8万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7966645
关键词：
Amino Acids Architecture Arts Blood Cancer Patient Candidate Disease Gene Cells Clinical Clinical Management Complex Computing Methodologies Constitutional DNA Data Diagnostic Neoplasm Staging Disease Epidemiology Epigenetic Process Event Gene Expression Genes Genetic Genetic Polymorphism Genome Genomics Goals Human Investigation Laboratories Lead Malignant Neoplasms Mammary Neoplasms Metastatic to Modification Molecular Mus Mutation Neoplasm Metastasis Orthologous Gene Outcome Pathway interactions Patients Pattern Planning Techniques Play Primary Neoplasm Process Publishing Research Role System Systems Biology Techniques Testing Tissues Tumor Tissue Work attributable mortality base cancer gene expression clinically relevant epidemiology study genetic risk factor human disease improved insight lymph nodes malignant breast neoplasm mouse model neoplastic cell prognostic research study theories tumor tumor progression

项目摘要

Recent progress in our laborabory has been significant. During the past two years we published the results of our first study of the effect of constitutional polymorphism influencing metastasis. We demonstrated that a single amino acid polymorphism in the gene Sipa1 could modulate the metastatic capacity of mouse mammary tumors by as much as ten-fold. Furthermore, we demonstrated, using pilot human epidemiology studies, that polymorphisms in the human ortholog of this gene, SIPA1, were associated with lymph node status in human breast cancer. These findings were the first published example that genetic inheritance rather than mutation within tumors, plays a major role in the progression of human cancer. Based on these results, we have extended our analysis to identify additional genes associated with metastatic breast cancer. Using a combination of techniques and strategies including genetics, whole genome analysis of gene expression, and human epidemiology, we have identified seven additional genes that appear to play a role in human breast cancer progression. Furthermore, molecular characterization of these genes demonstrated that several physically interact within cells, and all appear to be involved in a common gene expression network. A putative network of these genes has been assembled and tentatively titled the Diasporin network. Additional efforts have focused on the ability of these metastasis modifier genes to be used in clinical prognostic tests. Work in other laboratories has demonstrated that metastatic and non-metastatic breast cancers display different gene expression patterns, which can be used to predict the likelihood that a patient will progress to metastatic disease. Using publicly available human breast cancer gene expression data, we investigated the effect of each of our candidate genes to predict outcome. These experiments demonstrated that the metastasis modifier candidate genes were capable of inducing a predictive gene signature for human patients, and provided the first putative molecular basis for these clinically relevant tests. Current investigations include characterizations of additional candidate genes as well as further investigations into previously identified metastasis modifier genes. Ongoing work on the Diasporin pathway suggests that genetic modification of breast cancer metastasis may be the result of epigenetic changes with tumor cells. Additional efforts are focused on further characterization of the molecular basis of the clinical prognostic gene expression patterns. Using these complementary systems biology and systems genetics methodologies, we plan to continue our genetic and genomic analysis of the genome architecture associated with breast cancer tumor progression. The data generated in these studies will be further analyzed by state-of-the-art computational methods to further elucidate the complex interacting networks associated with metastatic progression.Recent progress in our laborabory has been significant. During the past two years we published the results of our first study of the effect of constitutional polymorphism influencing metastasis. We demonstrated that a single amino acid polymorphism in the gene Sipa1 could modulate the metastatic capacity of mouse mammary tumors by as much as ten-fold. Furthermore, we demonstrated, using pilot human epidemiology studies, that polymorphisms in the human ortholog of this gene, SIPA1, were associated with lymph node status in human breast cancer. These findings were the first published example that genetic inheritance rather than mutation within tumors, plays a major role in the progression of human cancer. Based on these results, we have extended our analysis to identify additional genes associated with metastatic breast cancer. Using a combination of techniques and strategies including genetics, whole genome analysis of gene expression, and human epidemiology, we have identified seven additional genes that appear to play a role in human breast cancer progression. Furthermore, molecular characterization of these genes demonstrated that several physically interact within cells, and all appear to be involved in a common gene expression network. A putative network of these genes has been assembled and tentatively titled the Diasporin network. Additional efforts have focused on the ability of these metastasis modifier genes to be used in clinical prognostic tests. Work in other laboratories has demonstrated that metastatic and non-metastatic breast cancers display different gene expression patterns, which can be used to predict the likelihood that a patient will progress to metastatic disease. Using publicly available human breast cancer gene expression data, we investigated the effect of each of our candidate genes to predict outcome. These experiments demonstrated that the metastasis modifier candidate genes were capable of inducing a predictive gene signature for human patients, and provided the first putative molecular basis for these clinically relevant tests. Current investigations include characterizations of additional candidate genes as well as further investigations into previously identified metastasis modifier genes. Ongoing work on the Diasporin pathway suggests that genetic modification of breast cancer metastasis may be the result of epigenetic changes with tumor cells. Additional efforts are focused on further characterization of the molecular basis of the clinical prognostic gene expression patterns. Using these complementary systems biology and systems genetics methodologies, we plan to continue our genetic and genomic analysis of the genome architecture associated with breast cancer tumor progression. The data generated in these studies will be further analyzed by state-of-the-art computational methods to further elucidate the complex interacting networks associated with metastatic progression.

我们实验室最近取得了重大进展。在过去的两年里，我们发表了第一项关于体质多态性影响转移的研究结果。我们证明，Sipa1 基因中的单个氨基酸多态性可以将小鼠乳腺肿瘤的转移能力调节多达十倍。此外，我们通过人类流行病学试点研究证明，该基因 SIPA1 的人类直系同源物的多态性与人类乳腺癌的淋巴结状态相关。这些发现是第一个发表的例子，表明基因遗传而不是肿瘤内的突变在人类癌症的进展中发挥着重要作用。基于这些结果，我们扩展了分析范围，以确定与转移性乳腺癌相关的其他基因。通过结合遗传学、基因表达的全基因组分析和人类流行病学等技术和策略，我们已经确定了另外七个似乎在人类乳腺癌进展中发挥作用的基因。此外，这些基因的分子特征表明，一些基因在细胞内发生物理相互作用，并且所有基因似乎都参与了一个共同的基因表达网络。这些基因的假定网络已经组装完毕，并暂定名为 Diasporin 网络。其他的努力集中在这些转移修饰基因用于临床预后测试的能力上。其他实验室的工作表明，转移性和非转移性乳腺癌表现出不同的基因表达模式，这可用于预测患者进展为转移性疾病的可能性。使用公开的人类乳腺癌基因表达数据，我们研究了每个候选基因对预测结果的影响。这些实验证明，转移修饰候选基因能够诱导人类患者的预测基因特征，并为这些临床相关测试提供了第一个假定的分子基础。目前的研究包括其他候选基因的表征以及对先前确定的转移修饰基因的进一步研究。正在进行的 Diasporin 通路研究表明，乳腺癌转移的基因修饰可能是肿瘤细胞表观遗传变化的结果。其他工作集中于进一步表征临床预后基因表达模式的分子基础。利用这些互补的系统生物学和系统遗传学方法，我们计划继续对与乳腺癌肿瘤进展相关的基因组结构进行遗传和基因组分析。这些研究中生成的数据将通过最先进的计算方法进行进一步分析，以进一步阐明与转移进展相关的复杂的相互作用网络。我们实验室最近取得了重大进展。在过去的两年里，我们发表了第一项关于体质多态性影响转移的研究结果。我们证明，Sipa1 基因中的单个氨基酸多态性可以将小鼠乳腺肿瘤的转移能力调节多达十倍。此外，我们通过人类流行病学试点研究证明，该基因 SIPA1 的人类直系同源物的多态性与人类乳腺癌的淋巴结状态相关。这些发现是第一个发表的例子，表明基因遗传而不是肿瘤内的突变在人类癌症的进展中发挥着重要作用。基于这些结果，我们扩展了分析范围，以确定与转移性乳腺癌相关的其他基因。通过结合遗传学、基因表达的全基因组分析和人类流行病学等技术和策略，我们已经确定了另外七个似乎在人类乳腺癌进展中发挥作用的基因。此外，这些基因的分子特征表明，一些基因在细胞内发生物理相互作用，并且所有基因似乎都参与了一个共同的基因表达网络。这些基因的假定网络已经组装完毕，并暂定名为 Diasporin 网络。其他的努力集中在这些转移修饰基因用于临床预后测试的能力上。其他实验室的工作表明，转移性和非转移性乳腺癌表现出不同的基因表达模式，这可用于预测患者进展为转移性疾病的可能性。使用公开的人类乳腺癌基因表达数据，我们研究了每个候选基因对预测结果的影响。这些实验证明，转移修饰候选基因能够诱导人类患者的预测基因特征，并为这些临床相关测试提供了第一个假定的分子基础。目前的研究包括其他候选基因的表征以及对先前确定的转移修饰基因的进一步研究。正在进行的 Diasporin 通路研究表明，乳腺癌转移的基因修饰可能是肿瘤细胞表观遗传变化的结果。其他工作集中于进一步表征临床预后基因表达模式的分子基础。利用这些互补的系统生物学和系统遗传学方法，我们计划继续对与乳腺癌肿瘤进展相关的基因组结构进行遗传和基因组分析。这些研究中生成的数据将通过最先进的计算方法进行进一步分析，以进一步阐明与转移进展相关的复杂的相互作用网络。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mouse modifier genes in mammary tumorigenesis and metastasis.

小鼠乳腺肿瘤发生和转移中的修饰基因。

DOI：
10.1007/s10911-008-9089-1
发表时间：
2008
期刊：
Journal of mammary gland biology and neoplasia
影响因子：
2.5
作者：
Winter,ScottF;Hunter,KentW
通讯作者：
Hunter,KentW

Introduction to special issue on 'epigenetic and physiological regulation of metastasis'.

“转移的表观遗传和生理调控”特刊简介。

DOI：
10.1007/s10585-008-9211-1
发表时间：
2009
期刊：
Clinical & experimental metastasis
影响因子：
4
作者：
Hunter,Kent;Chambers,AnnF
通讯作者：
Chambers,AnnF

Mechanisms of metastasis.

DOI：
10.1186/bcr1988
发表时间：
2008
期刊：
BREAST CANCER RESEARCH
影响因子：
7.4
作者：
Hunter, Kent W;Crawford, Nigel P S;Alsarraj, Jude
通讯作者：
Alsarraj, Jude

Genetic variation in SIPA1 in relation to breast cancer risk and survival after breast cancer diagnosis.

DOI：
10.1002/ijc.23919
发表时间：
2009-04-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Gaudet, Mia M.;Hunter, Kent;Pharoah, Paul;Dunning, Alison M.;Driver, Kristy;Lissowska, Jolanta;Sherman, Mark;Peplonska, Beata;Brinton, Louise A.;Chanock, Stephen;Garcia-Closas, Montserrat
通讯作者：
Garcia-Closas, Montserrat

A systems biology approach to defining metastatic biomarkers and signaling pathways.

定义转移生物标志物和信号通路的系统生物学方法。