Modifiers of Intestinal Tumor Progression

肠肿瘤进展的调节因素

• 批准号: 8131384
• 负责人: Linda D Siracusa
• 金额: $ 16.85万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8131384
• 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; 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; Pattern; 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; 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。虽然接受结肠镜检查的人数在增加，但结直肠癌的发病率并没有下降。小肠癌占结直肠癌的不到5%，但五年生存率很低。家族性腺瘤性息肉病（FAP）是一种显性遗传疾病，易使个体发生结直肠癌，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（格罗登等人，1991）。患有FAP也是小肠癌的一个危险因素，因为肿瘤倾向于在FAP患者的十二指肠或十二指肠附近形成。小肠癌和结直肠癌的小鼠模型对于理解肿瘤发生的过程和发现干扰恶性进展的机制是非常宝贵的。ApcMin/+小鼠在Apc基因中含有点突变，导致蛋白质截短（Moser et al. 1990; Su et al. 1992）。遗传背景在确定ApcMin/+小鼠的表型方面具有重要作用（综述见Siracusa et al. 2004），复杂性状分析已鉴定出几个改变肠道肿瘤表型的Min（Mom）基因座修饰因子（综述见Kwong and Dove 2008）。该探索性R21的重点是使用ApcMin/+小鼠模型来鉴定影响肿瘤进展的基因。这项研究的想法是在我们有一个令人兴奋的发现时产生的，即来自近交系之间互交的杂交后代具有很长的寿命，并且对肿瘤进展具有高度抵抗力，即使它们携带ApcMin突变。在这些特殊的小鼠中发展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，我们有一个独特的模型系统，以几种方式模拟人类疾病：1）这些杂交小鼠的基因组实际上在每个位点都是杂合的（与人类的情况一样），2）这些小鼠的寿命与50岁及以上的人类相当（肠癌的风险因素），和3）肿瘤发展而不丢失携带Apc+等位基因的整个染色体（与人类肿瘤相似的机制）。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，最终可能会为肠癌提供更好的预防和治疗选择。 公共卫生相关性：许多步骤和变化沿着的方式是负责把一个良性肿瘤生长成危及生命的癌症。这项研究旨在揭示在这一过程的中间步骤中发挥作用的基因。目标是确定可以防止肿瘤发展为小肠和结肠癌的基因。有了这些知识，我们可以为患者开发新的预防和治疗方案。