Identifying Inborn Genetic Susceptibility to Development of Cancer Metastasis

识别癌症转移发展的先天遗传易感性

• 批准号: 8530979
• 负责人: SANFORD D. MARKOWITZ
• 金额: $ 95.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8530979
• 关键词: Accounting; Alleles; Biological; Cancer Etiology; Cancer Prognosis; Cancer Relapse; Cause of Death; Cessation of life; Colon Carcinoma; Development; Disease; Disseminated Malignant Neoplasm; Distant; Early Diagnosis; Ethnic group; Excision; Frequencies; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Markers; Genetic Models; Genetic Predisposition to Disease; Individual; Laboratories; Malignant Neoplasms; Modeling; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Pathway interactions; Persons; Population; Predisposition; Resistance; Site; Solid Neoplasm; Susceptibility Gene; Techniques; Testing; Time; United States; Variant; anti-cancer therapeutic; cancer cell; cancer genetics; cancer genome; cancer therapy; genetic variant; genome wide association study; killings; novel; resistance factors; tumor; tumor progression

DESCRIPTION (provided by applicant): This proposal advances the novel paradigm that cancer metastasis, the ultimate cause of death from this disease, may crucially depend on inborn genetic susceptibility factors. Stated otherwise: certain individuals who develop cancer may have good outcomes because they were born inherently resistant to cancer's spread; whereas, other individuals who succumb to cancer may do so due to having an inborn susceptibility to cancer's metastatic spread. We will test this new paradigm in colon cancer, the second leading cause of cancer deaths in the United States, with 150,000 new cases annually, of whom one-third, or 50,000, die because of developing cancer metastasis. We advance this new paradigm because studies from our laboratory show that the existing paradigm, that cancers progress by the cancer cell's multi-step accumulation of increasing numbers of genetic alterations, manifestly fails to explain the final lethal step of colon cancer's metastasizing to distant organ sites. Specifically, our studies sequencing the complete "cancer genomes" of metastatic and primary colon cancers unexpectedly, but clearly, show that no new mutations are required to generate a colon cancer metastases from a preceding primary colon cancer tumor. These findings directly challenge the paradigm that has dominated cancer genetics for over two-decades. If new gene mutations do not cause cancer metastasis, what then accounts for the difference between the one-third of colon cancers that metastasize and kill, versus the two-thirds that do not? We posit that inborn genetic susceptibility factors that would be common in the population are the major missing factor accounting for difference between persons in whom cancers spread versus those in whom it does not. By analogy, this model extends to cancer metastasis the finding that host genetic resistance factors can be key determinants of survival from potentially lethal infectious challenges. Specifically, this application will identify genetic markers of metastasis susceptibility by using the technique of a whole genome association study to compare the frequency of over 1,000,000 genetic variants between individuals whose colon cancers never metastasized (non-metastatic cases), versus individuals whose colon cancers were metastatic at the time of diagnosis (early-metastatic cases), and versus individuals whose colon cancers relapsed and metastasized following initial complete surgical resections (late-metastatic cases). From these genetic markers of colon cancer metastasis susceptibility we will elucidate the underlying metastasis susceptibility genes, identify the causative metastasis susceptibility variants present in these genes among different ethnic groups, determine if these variants or genes also impart susceptibility to metastasis in other common solid tumors, and determine the biologic pathways by which these susceptibility alleles promote cancer metastasis. Establishing this new paradigm for how cancers spread and kill will yield novel gene targets for cancer prognosis, cancer management, and for development of new anti-cancer therapeutics.

描述（由申请人提供）：该提案推动了新的范式，即癌症转移是这种疾病的最终死亡原因，可能至关重要地取决于先天的遗传易感性因素。否则说：某些发展癌症的人可能会产生良好的结果，因为他们天生就对癌症的传播具有抗药性。而其他屈服于癌症的人可能会因为对癌症转移性传播具有天生的敏感性。我们将在结肠癌中测试这种新的范式，这是美国癌症死亡的第二大原因，每年有15万例新病例，其中三分之一或50,000例由于癌症转移而死。我们推进了这个新的范式，因为我们实验室的研究表明，通过癌细胞越来越多的遗传变化数量的多步积累，现有的范例显然无法解释结肠癌转移到远处的器官的最终致命步骤。具体而言，我们的研究对转移性和原发性结肠癌的完整“癌症基因组”进行了测序，但很明显，不需要新的突变即可从先前原发性结肠癌癌症中产生结肠癌转移。这些发现直接挑战了超过两个十年的癌症遗传学的范式。如果新基因突变不会引起癌症转移，那么这是什么原因解释了转移和杀死的三分之一的结肠癌与没有转移和杀死的癌症之间的差异？我们认为，在人口中常见的先天遗传敏感性因素是癌症传播与没有的人之间的差异的主要缺失因素。通过类比，该模型扩展到癌症转移的发现，即宿主遗传抗性因子可能是潜在致命感染挑战的关键决定因素。 Specifically, this application will identify genetic markers of metastasis susceptibility by using the technique of a whole genome association study to compare the frequency of over 1,000,000 genetic variants between individuals whose colon cancers never metastasized (non-metastatic cases), versus individuals whose colon cancers were metastatic at the time of diagnosis (early-metastatic cases), and versus individuals whose colon cancers relapsed and metastasized following initial complete手术切除术（晚期转移病例）。从这些结肠癌转移易感性的这些遗传标记中，我们将阐明潜在的转移易感性基因，确定这些基因中不同种族中这些基因中存在的病变转移易感性变异，这些变体或基因在其他常见的实体瘤中是否也促进了这些变体或基因对其他癌症的疾病的易感性，并促进了这些癌症。建立有关癌症如何传播和杀死的新范式将产生新的基因靶标，以实现癌症预后，癌症管理以及新的抗癌治疗剂的发展。