Modifiers of Intestinal Tumor Progression

肠肿瘤进展的调节因素

• 批准号: 8230472
• 负责人: Linda D Siracusa
• 金额: $ 20.23万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230472
• 关键词: Adenocarcinoma; Adenomatous Polyposis Coli; Age; Age-Years; Aging; Alleles; Backcrossings; Benign; Biological Assay; Biological Models; Candidate Disease Gene; Chromosomes; Colon; Colonoscopy; Colorectal Cancer; Columbidae; Complex; Development; Disease; Duodenum; Environment; Female; Gene Expression Profile; Generations; Genes; Genetic; Genome; Goals; Human; Hybrids; Inborn Genetic Diseases; Inbred Strain; Incidence; Individual; Intestinal Cancer; Intestinal Neoplasms; Intestinal Polyps; Intestines; Knowledge; Lead; Life; Location; Longevity; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mammary Neoplasms; MicroRNAs; Modeling; Mus; Mutate; Mutation; Normal tissue morphology; Pathway interactions; Patients; Phenotype; Point Mutation; Prevention; Preventive; Process; Protein Truncation; Proteins; Radiation; Research; Resistance; Risk Factors; Role; Screening procedure; Small Intestines; Staging; Study models; Survival Rate; Therapeutic; Transcript; Translations; Tumor Suppressor Genes; Variant; Work; adenoma; cancer diagnosis; congenic; consomic; design; gene function; genetic variant; high throughput screening; human disease; male; malignant small intestine tumor; mouse model; novel; prevent; public health relevance; research study; trait; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Cancers of the gastrointestinal tract comprise more than 10% of all cancers diagnosed in the U.S. (www.cancer.org). Disease incidence and phenotype are influenced by genetics and the environment. Although the number of people having colonoscopy screenings is increasing, the incidence of colorectal cancer has not decreased. Cancers of the small intestine total less than 5% of colorectal cancers, but the five year survival rate is very low. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), a dominant inherited disorder that predisposes individuals to developing colorectal cancer (Groden et al. 1991). Having FAP is also a risk factor for small intestinal cancer, as tumors tend to form at or near the duodenum in FAP patients. Mouse models of small intestine and colorectal cancers are invaluable for understanding the process of tumorigenesis and discovering mechanisms that interfere with progression to malignancy. The ApcMin/+ mouse contains a point mutation in the Apc gene that results in a truncated protein (Moser et al. 1990; Su et al. 1992). Genetic background has a significant role in determining the phenotypes of ApcMin/+ mice (reviewed in Siracusa et al. 2004) and complex trait analyses have identified several Modifier of Min (Mom) loci that alter intestinal tumor phenotypes (reviewed in Kwong and Dove 2008). This exploratory R21 is focused on using the ApcMin/+ mouse model to identify genes that influence tumor progression. The idea for this study arose when we had an exciting finding, namely that hybrid progeny from an intercross between inbred strains had a long lifespan and were highly resistant to tumor progression, even though they carried the ApcMin mutation. The few tumors that develop in these exceptional mice remain almost exclusively low grade adenomas and do not progress to more advanced stages. This model challenges the existing paradigm that tumor progression is a function of age. We, therefore, have a unique model system that mimics human disease in several ways: 1) the genome of these hybrid mice is heterozygous at virtually every locus (as is the case in humans), 2) the lifespan of these mice is comparable to humans 50 years of age and beyond (a risk factor for intestinal cancers), and 3) tumors develop without losing the entire chromosome carrying the Apc+ allele (a mechanism similar to human tumors). The factor responsible for resistance to progression appears limited to a single chromosome; our research is designed to define this modifier gene and pathways that protect against tumor progression. Translation of this work to human cancers could ultimately lead to better prevention and treatment options for intestinal cancers. PUBLIC HEALTH RELEVANCE: Many steps and changes along the way are responsible for turning a benign tumor growth into a life-threatening cancer. This research is designed to uncover genes that function during the intermediate steps of this process. The goal is to identify genes that can prevent the progression of tumors into cancers in the small intestine and colon. With this knowledge, we can move towards developing novel preventive and therapeutic options for patients.

描述（由申请人提供）：胃肠道癌症占美国诊断的所有癌症的 10% 以上 (www.cancer.org)。疾病的发病率和表型受遗传和环境的影响。尽管接受结肠镜检查的人数不断增加，但结直肠癌的发病率并未下降。小肠癌总数不到结直肠癌的5%，但五年生存率很低。家族性腺瘤性息肉病 (FAP) 中的腺瘤性结肠息肉病 (APC) 肿瘤抑制基因发生突变，这是一种显性遗传性疾病，使个体易患结直肠癌 (Groden et al. 1991)。患有 FAP 也是小肠癌的危险因素，因为肿瘤往往在 FAP 患者的十二指肠处或附近形成。小肠癌和结直肠癌的小鼠模型对于了解肿瘤发生过程和发现干扰恶性肿瘤进展的机制具有不可估量的价值。 ApcMin/+ 小鼠的 Apc 基因存在点突变，导致蛋白质被截短（Moser 等人，1990 年；Su 等人，1992 年）。遗传背景在确定 ApcMin/+ 小鼠的表型方面具有重要作用（Siracusa 等人于 2004 年进行了综述），并且复杂的性状分析已确定了几个改变肠道肿瘤表型的 Min (Mom) 修饰基因座（Kwong 和 Dove 于 2008 年进行了综述）。该探索性 R21 的重点是使用 ApcMin/+ 小鼠模型来识别影响肿瘤进展的基因。当我们有一个令人兴奋的发现时，我们产生了这项研究的想法，即近交系之间杂交产生的杂种后代具有较长的寿命，并且对肿瘤进展具有高度抵抗力，即使它们携带 ApcMin 突变。在这些特殊小鼠中形成的少数肿瘤几乎完全是低级别腺瘤，并且不会进展到更晚期。该模型挑战了肿瘤进展是年龄函数的现有范式。因此，我们拥有一个独特的模型系统，可以通过多种方式模拟人类疾病：1）这些杂交小鼠的基因组几乎在每个位点都是杂合的（就像人类的情况一样），2）这些小鼠的寿命与 50 岁及以上的人类相当（肠癌的危险因素），3）肿瘤的发展没有丢失携带 Apc+ 等位基因的整个染色体（类似于人类的机制） 人类肿瘤）。负责抵抗进展的因素似乎仅限于单个染色体；我们的研究旨在定义这种修饰基因和防止肿瘤进展的途径。将这项工作转化为人类癌症最终可能会带来更好的肠癌预防和治疗选择。 公众健康相关性：过程中的许多步骤和变化导致良性肿瘤生长转变为危及生命的癌症。这项研究旨在揭示在此过程的中间步骤中发挥作用的基因。目标是确定可以阻止肿瘤进展为小肠和结肠癌的基因。有了这些知识，我们就可以为患者开发新的预防和治疗方案。